INVESTIGATOR RESPONSIBILIITES

ICRI Cranfield

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Definitions

Investigator A person responsible for conduct of

the trial at a trial site.

Sub investigator (Co-investigator)Individual member of a CT team,

designated & supervised by the Investigator to perform trial related procedures & to take trial related decisions 2

beforeduring a clinical trial after

INVESTIGATOR RESPONSIBILIITES

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BEFORE STUDY START I

Adequately qualified, trained and experienced actual updated CVFamiliar with the trial protocol, IB, product information etc.Familiar with GCP and applicable regulationsPermit monitoring, auditing and inspectionsDelegations of trial procedures must be documented site signature log

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Adequate resources: - sufficient patients in the applicable

indication and time period - sufficient time and capacities - Qualified staff and facilities

Adequate study information (protocol,medication,procedures) to study team(sub-investigator, study nurses etc.)Adequate medical care to trial subjects during and after the trial

BEFORE STUDY START II

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Obtain a written and dated positive ethics vote for the protocol, patient information and consent form, recruitment material and any other written information provided to the subjectsProvide the ethics committee with a current Investigator’s BrochureDeclare appropriate conduct of the study according to the protocol, GCP and applicable regulations by signing the protocol

BEFORE STUDY START III

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Regulatory Significance of Form FDA 1572( financial disclosure)

•FDA 1572 = official statement of the investigator's commitments under the U.S. code of Federal Regulations.

•reference for the FDA when seeking addresses of potential sites of inspection

•Investigator provides the Form FDA 1572 to sponsor as a prerequisite to lawful participation in an IND study

•All information should be current and accurate. 7

DURING THE STUDY I

Documentation and explaining all protocol deviations and informing the sponsor,regulatory agencies and ethics committees accordingly (allowed only in the case of immediate hazards to the trial subjects implementation of a protocol amendments if applicable)

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Documentation of study medication, including batch number, expiry date etc.

- supply to the site • supply to the patients• Use by the patient• return from the patient

- stock on site- Return to the sponsor/destruction on site

DURING THE STUDY II

Drug

accountability

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Adequate storage and handling of study medicationEnsure adequate usage of the study medication by trial subjects only and as specified in the protocolFollow randomization scheme/proceduresObtain informed written consent from each trial subject prior to study participationAdequate medical careAccurate and timely reporting of trial data

DURING THE STUDY III

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Maintain source data on medical care provided to the subject during the clinical trialEnsure CRF data consistent with the source documentsExplain inconsistencies between source data and CRF recordsCRF corrections must be dated, initialled and explained (written and electronic records)

DURING THE STUDY IV

Audit trail 11

Filing of Essential Documents Provide direct access to source documents to monitors, auditors and inspectorsObtain ethical approval for protocol amendments and study document updatesProvide annual study reports to the ethics committee, as specified in the approval

DURING THE STUDY V

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Report all serious adverse events immediately to the sponsor (specifications as detailed in the protocol)Report all serious unexpected adverse reactions to the ethics committee

DURING THE STUDY VI

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Provide ongoing medical care to the trial subjectsIn the case of a premature termination inform the patients and ethics committeeOtherwise provide a summary of study results to the ethics committee

AFTER STUDY TERMINATION I

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Archiving of study documents- patient identification- Written consent forms- All relevant source documents - Copies of CRFs- Investigator binder- And other relevant study documents

AFTER STUDY TERMINATION II

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Good Clinical Practice and the

INVESTIGATOR

Investigator

Regulatory Compliance

Ethics Approval

Informed Consent

Medical CareStaff Supervision

Investigational Product

Safety Reporting

Records Reports

Monitoring /Audit

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INVESTIGATOR - IMPACT

Increased responsibility for documentationIncreased communication Increased paper work?Increased accountability

Resulting in more………..?

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PATIENT RECRUITMENT AND RETENTION IN CLINICAL TRIALS

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Introduction

Patient recruitment efforts are becoming increasingly sophisticated to accommodate enrollment demands linked to the rising number of global clinical trials. Active investigational new drug applications (INDs) are approaching 4,000 per year, the number of subjects per NDA currently exceeds 5,300 and approximately 80,000 clinical trials are ongoing in the United States alone. Attracting, enrolling and retaining study subjects in many of these trials is a challenge, and meeting that challenge successfully in accordance with established timelines requires well-designed initiatives by trained staff or professional recruitment providers.

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It is estimated that for a new molecule that is discovered it would take approximately 10-15 years to reach the market at an approximate cost of $500-800 million. Of these 10-15 years, it is estimated that recruitment of subjects takes up 30 percent of clinical timelines. Therefore, recruiting of appropriate subjects is an issue that must be considered before the study and throughout the duration of the study and investigators must be realistic when determining feasibility or recruiting patients into a particular study.

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The need for staff training in Patient Recruitment

Training in patient recruitment is the best practice and is strongly needed by investigative sites to increase their skills in developing comprehensive recruitment campaigns.

Training in patient recruitment should focus on a wide range of proactive strategies that address project feasibility, resource planning, return on investment (ROI) assessment, regulatory and ethical issues and media planning.

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Budgeting and contracting in Patient Recruitment

Creating a patient recruitment budget and considering contracting options are becoming ever more essential in the highly competitive and rapidly growing field of clinical trials. To successfully plan and execute patient recruitment budgets and contracts, there are several essential considerations.

Prioritizing a patient recruitment budget around strategic, research and development considerations are crucial components of successful budgets.

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Creating a study profile and projecting a recruitment funnel from the framework on which a budget is built. Recognizing the importance of timing in creating a budget cannot be overemphasized in its effect on the scope and size of expenditures. When actually drafting the budget, all elements must be considered and the possibility of future changes incorporated into a contingency budget.

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Patient Recruitment

Ethical and regulatory interpretation assumes recruitment of subjects as the beginning of the informed consent process engaging/inviting potential subjects to participate in the research.

However, three realities pervade recruitment as it is now practiced:

Subjects can either be viewed as commodities or as offering a gift of themselves;

Recruitment includes retention in order to achieve the primary goal of clinical research: clean data; and,

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Recruitment and retention pose a significant threat to achieving “quality speed.”

A Harris Interactive Survey reported that of patients who are aware of an appropriate clinical trial, 71 percent of eligible patients choose not to participate. Reasons for not participating could be risk of side-effects, concern about getting placebo, center too far away, unable to find trial, not eligible, inconvenient hours, and/or not enough information. 25

Ethical issues in Patient Recruitment

Recruiting subjects, therefore, confronts ethical issues associated both with study start-up and with different phases. The principle that appears to be violated when potential subjects enter studies based on misinformation, intentional or inadvertent, is undue influence. One of the ethical issues in patient recruitment is confidentiality and privacy of personal health information. As a part of the recruitment process an investigator has access to a patient’s health information. In order to use a patient’s PHI an authorization from the patient is mandatory. Hence, today, all informed consent forms carry a statement indicating that the patient’s PHI will be shared with the monitor and other staff involved in the research work.

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Major sources of Patient Recruitment

Although patients are often recruited for clinical trials from the medical practice of the investigator, there are numerous occasions when this is either not possible or is not the sole source of patient recruitment. A series of articles dealing with recruitment of patients from various other sources are:

Govt. employees (ex: military). Private industry (ex: clinics in large industries) Medical referrals from professional colleagues (i.e., from

direct contact). Referrals from clinical laboratories. Mass media strategies (via newspaper or radio

advertisements).27

Mass mailings. Community screening (ex: health fairs). Participants in other clinical studies. Blood banks (blood donors). Local advertisements (notices on bulletin

boards) Other sources.

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Patient Recruitment Plan

For most clinical trials, patient recruitment follows this process:

Recruitment effort by which the research team informs the community of the clinical trial

Initial patient eligibility screening on the phone or at the study site

Obtaining informed consent More detailed eligibility screening at the study

site Patient registration

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Administering the protocol A detailed plan for patient recruitment should be

developed before a clinical trial starts.  Because patient recruitment takes concerted efforts from everyone on the research team, it is important that all research team members be actively involved in developing the plan and that they all agree to the strategies and methods to be used.  This creates ownership of the recruitment plan among team members and promote adherence to the recruitment procedures. 30

Contd….

There are seven steps in developing a patient recruitment plan:

1. Identify the no. of patients to be recruited.2. Identify potential referral base(s).3. Determine methods for approaching each source.4. Determine the process for patient enrollment.5. Document the patient recruitment plan.6. Define evaluation criteria for patient recruitment plan.7. Administer recruitment plan and view the plan

regularly.31

Methods of Patient Recruitment

Enrollment of a patient is only the first step towards the successful completion of a study. 

Direct Approaches like through internet, brochures and posters at various sites, talks to various groups, stories and advertisements in media like TV, radio, newspapers, magazines, etc.

Indirect approaches include Letters to solicit referrals, seminars in hospitals, notices on Bulletin boards, notices in journals, letters to journals, talks at local and State Medical Societies, talks at professional societies, and exhibits at conferences.

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Patterns of Patient Enrollment

All patients may be enrolled at one time (ex: in pharmacokinetic trials).

Patients may be enrolled on an ad hoc basis until a fixed date occurs.

Patients may be enrolled on an ad hoc basis until a fixed number are enrolled either at the site or at all sites combined.

Patients may be enrolled in pre-specified groups (ex: eight patients in group I followed by eight patients in group II, and so on).

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Methods and Approaches to enhance Patient Enrollment

Determine what is motivating patients to enter (as well as not to enter) a clinical trial and attempt to address patient needs.

Inform referring physicians that their patients may receive medical treatment not otherwise available.

Determine if inadequate patient enrollment relates primarily to patients, investigators, protocol, facilities, or other factors.

Place signs about the clinical trial in places where both physicians and potential patients may see them.

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Ask the investigator’s staff to review hospital admission or clinical appointments to seek potential patients.

Modify the inclusion criteria after determining which changes would not affect the clinical trial and yet would increase patient enrollment.

Increase the number of trial sites in a multicenter clinical trial.

Have a major well-respected expert come to a site with low enrollment and encourage physicians to refer or enter patients into the clinical trial.

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Provide a tour of the clinic for prospective patients and answer their questions.

Devote more time to recruitment and give it a high priority in terms of efforts.

Attempt to find populations of patients that may be accessed.

Provide funds to a hospital for supporting meetings, dinners, or texts, to be allocated at the hospitals (or investigators) discretion.

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Increase financial incentives for investigators or patient to improve recruitment.

Contact sources of other patient populations. Simplify the protocol in those areas in which

patient or investigators complain. Increase the duration of the recruitment

period. Provide more feedback to referring

physicians about the clinical trial and the status of the patients they have referred or will refer.

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Retention of Study Subjects (patients)

The only thing harder than recruiting patients is retaining them in a study. Just as recruitment of study volunteers needs careful planning and well developed strategies, retention of patients for the study duration also needs and deserves attention as a very high dropout rate would make a study statistically invalid. Overall dropout rates for a study are approximately 25 percent. This rate increases to 30 percent for phase III studies due to their long time commitments. All clinical trial participants have the right to drop out of the study at any time. 

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There are many ways in which a site can encourage its participants to remain in the study until the end.  Here are a few practical tips:

Show the participant they are respected and valued for their commitment throughout the study and the follow-up

Be flexible when scheduling visits and testing Keep participants informed of study progress

and results 39

Keep referring clinicians informed of participants' treatment, progress, and adverse events, so they can help provide emotional support to participants and answer participants' questions

Be sensitive to participants/small children and provide toys and books for children if possible

Make reminder phone calls and/or send written reminders regarding upcoming appointments or follow-up visits. 

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Lasagna’s Law: A central issue in Patient Recruitment

It was one of the pioneers in clinical pharmacology, the American Louis Lasagna, who described in 1970, a today's still well-known phenomenon in clinical trials: The incidence of patient availability sharply decreases when a clinical trial begins and returns to its original level as soon as the trial is completed. For illustration, in 1979 Lasagna commented on a trial where out of 8'000 patients theoretically available just 100 patients in the end participated. Later this phenomenon was popularly called Lasagna's Law.

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The major reason for the overly optimistic projection of available patient numbers relates to narrow in- and exclusion criteria which prevent many patients from enrolling that the investigator initially considered as viable subjects for the trial.

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Initiation of Trial

Completion of a Trial

Low

High

Availability of Suitable Patients to be enrolled in a clinical trial

Time

LASAGNA’S LAW43

Special Patient Population

While it can be challenging to reach a general audience for clinical trials, it is much more difficult to target "special populations" and motivate them to participate. Special populations are defined as specific ethnic and demographic groups, and the special population are arbitrarily divided into four groups:

1. Populations based on chronological age.2. Populations based on inherent characteristics of each

patient.3. Populations based on physiological characteristics of each

patient.4. Populations based on acquired characteristics of each

patient.44

Contd….

Problems & barriers in recruiting Special Populations are:

1. Ethical considerations 2. Cultural issues 3. Population pool 4. Health insurance 5. Caregivers as decision makers

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Solutions are

Understanding the process Informed consent and ethical concerns Market research and media consumption

patterns The right communication vehicles Geographical considerations

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