Question26: Please prepare an informed consent form for the imaginary drug Happymycin that would treat Mood Disorders (Depressions) ?
Answer:
INFORMED CONSENT FORM
You are invited to participate in a study of Happymycin. We hope to discover whether the drug Happymycin can treat mood disorder or not. You were selected as a possible participant in this study because you are suffering from mood disorder, between age 18 -60 yrs and willing to give informed consent.If you decide to participate, we will put you on either placebo or test drug to find out the effectiveness of the drug this procedure will take 24 months to be followed.You may experience some of the following side effects:
Dry mouth
Urinary retention
Blurred vision
Constipation
Sedation (can interfere with driving or operating machinery)
Sleep disruption
Weight gain
Headache
Nausea
Gastrointestinal disturbance/diarrhea
Abdominal pain
Inability to achieve an erection
Inability to achieve an orgasm (men and women)
Loss of libido
Agitation
Anxiety
The benefit you might achieve from the test drug are as follows improvement in mood, reduction in depression episodes or stoppage of depressive episodes, peaceful sleeps, improvement in ability to perform a task and increase memory.
There are several antidepressant drugs available in the market which you can use as an alternate of this procedure such as :
You are making a decision whether or not to participate. Your signature indicates that you have read the information provided above and have decided to participate. You may withdraw at any time without penalty or loss of benefits to which you may be entitled after signing this form
should you choose to discontinue participation in this study.
Q23: Please prepare a draft of the IB for the imaginary drug Happymycin that would treat Mood Disorders (Depressions) . Please include all appropriate parts according to ICHGCP?
Answer:
Please find below the draft of the investigator’s brochure for the imaginary drug Happymycin.
Happymycin is prescribed for the treatment of schizophrenia, a mental disorder marked by delusions (false beliefs), hallucinations, disrupted thinking, and loss of contact with reality. It is also used for the short-term treatment of mania associated with bipolar disorder.
Introduction Happymycin is the first in a new class of antipsychotic medications. Researchers believe that it works by diminishing the action of dopamine and serotonin, two of the brain’s chief chemical messengers.
Happymycin may cause tardive dyskinesia, a condition characterized by uncontrollable muscle spasms and twitches in the face and body. This problem can be permanent, and appears to be most common among older adults, especially women.
4. Physical, Chemical, and Pharmaceutical Properties and Formulation
5. Nonclinical Studies
5.1 Nonclinical Pharmacology
5.2 Pharmacokinetics and Product Metabolism in Animals
5.3 Toxicology
6 Effects in Humans
6.1 Pharmacokinetics and Product Metabolism in Humans
6.2 Safety and Efficacy
6.3 Marketing Experience
7 Summary of Data and Guidance for the Investigator
Question23: Please write a draft of the protocol summary for the imaginary drug Happymycin that would treat Mood Disorders (Depressions). Please include all appropriate parts according to ICH GCP.
Summary .
Aim:
The aim of this study is to establish the efficacy of the drug Happymycin to Placebo.
Title: Safety, Tolerability, and Efficacy of Happymycin in Patients with severe Mood disorders: A Double-Blind Placebo-Controlled Randomized
Trial Number: 03-N-0057
Protocol Number: 01-S-0357
Summary: This study will test the safety and effectiveness of the drug Happymycin in treating a Bipolar mood disorder Patients with MGUS have an abnormal protein called monoclonal IgM immunoglobulin that attacks the myelin sheath (protective coating) of nerves, causing them to not function properly. The disease affects the nerves in the legs or arms, and patients have numbness, tingling, muscle weakness, and unsteady gait. There are no adequate treatments. Immunosuppressive drugs or human immunoglobulin infusions can produce mild and transient improvement, but the benefits of these therapies are not significant.
Bipolar disorder is a psychiatric diagnosis that describes a category of mood disordersdefined by the presence of one or more episodes of abnormally elevated mood clinically referred to as mania or, if milder, hypomania. Individuals who experience manic episodes also commonly experience depressive episodes or symptoms, or mixed episodes in which features of both mania and depression are present at the same time Episodes of abnormality are associated with distress and disruption, and an elevated risk of suicide, especially during depressive episodes. Bipolar disorder is often treated with anti-manic, and sometimes other, psychiatric drugs. Psychotherapy may have an important role, as well as personal recovery work,
Bipolar disorders are associated with imbalances in certain chemicals that carry signals between brain cells (neurotransmitters). These chemicals include serotonin, norepinephrine, and dopamine. Happymycin is approved to balance these chemical neurotransmitters.
Although the number of patients treated with Happymycin was small, the drug was well tolerated and caused significant improvement in several of the patients
Patients 25 years of age and older with bipolar disorder may be eligible for this 2-year study. candidates will be screened with a medical history, physical and neurological examinations,
Participants will be randomly assigned to either Happymycin or placebo once a week for 4 consecutive weeks. In addition, they will undergo the following tests and procedures:
-Monthly follow-up visits following Happymycin treatment for repeat physical and neurological examinations, blood tests, muscle strength measurements, and review of signs and symptoms.
-Two sessions of ESR tests, one at the beginning of the study and one a year later-to collect blood.
CT scan can are done once at beginning of study and one at end.
If this study indicates that Happymycin is beneficial against bipolar disorder , patients who were assigned to receive placebo during the trial will be offered treatment with Happymycin (four weekly infusions) at the end of the study.
Sponsoring Institute:
Research Center of Neurological Disorders
Recruitment Detail
Type : Active Accrual Of New Subjects
Gender: Male & Female
Referral Letter Required: Yes
Population Exclusion(s): Children
Eligibility Criteria:
INCLUSION CRITERIA:
Patient having Bipolar disorder.
Willingness and legal ability to give and sign informed study consent.
Willingness to travel to National Institutes of Health (NIH) for scheduled protocol studies and treatment.
Men and women of reproductive potential must agree to use an acceptable method of birth control during treatment and for six months after completion of treatment.
Adequate bone marrow, renal, and liver function
EXCLUSION CRITERIA:
Immunosuppressive drug therapy at the time within 6 months prior to enrollment. Specifically, candidates may not be taking prednisone, cyclosporine, tacrolimus, azathioprine, mycophenolate mofetil, anti-lymphocyte agents, cyclophosphamide, methotrexate, or other agents whose therapeutic effect is immunosuppressive or could provoke neuropathy as undesirable secondary effect.
Any medical or social condition that precludes follow-up visits.
Platelet count less than 100,000/mm(3).
Hemoglobin less than 7.0 mg/dl.
Any known immunodeficiency syndrome included HIV infection.
Systematic edema or pulmonary edema.
Any condition that would likely increase the risk of protocol participation or confound the interpretation of the data including active infections.
Pregnancy. Serum pregnancy test will be performed and must be negative in all women of childbearing potential enrolled in this study.
Patients below the age of 25 because this disorder does not occur in such age groups.
Special Instructions: Currently Not Provided
Keywords:
Drug(s):
Question22: What are general responsibilities of the sponsor in clinical trials according to ICH GCP?
Answer:
Following are the key responsibilities of the sponsor in in clinical trial according to ICH GCP.
Data Management and Record Keeping:
The sponsor should utilize appropriately qualified individuals to supervise the overall conduct of the trial, to handle the data, to verify the data, to conduct the statistical analyses, and to prepare the trial reports.
When using electronic trial data handling and/or remote electronic trial data systems, the sponsor should:
a. Ensure and document that the electronic data processing system(s) conforms to the sponsor’s established requirements for completeness, accuracy, reliability, and consistent intended performance (i.e., validation).
b. Maintains SOPs for using these systems.
c. Ensure that the systems are designed to permit data changes in such a way that the data changes are documented and that there is no deletion of entered data (i.e., maintain an audit trail, data trail, edit trail).
d. Maintain a security system that prevents unauthorized access to the data.
e. Maintain a list of the individuals who are authorized to make data changes.
f. Maintain adequate backup of the data.
g. Safeguard the blinding, if any (e.g., maintain the blinding during data entry and processing).
The sponsor-specific essential documents should be retained until at least 2 years after the last approval of a marketing application in an ICH region and until there are no pending or contemplated marketing applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical development of the investigational product. These documents should be retained for a longer period however if required by the applicable regulatory requirement(s) or if needed by the sponsor.
The sponsor should inform the investigator(s)/institution(s) in writing of the need for record retention and should notify the investigator(s)/institution(s) in writing when the trial related records are no longer needed.
Investigator Selection:
The sponsor is responsible for selecting the investigator(s)/institution(s). Each investigator should be qualified by training and experience and should have adequate resources to properly conduct the trial for which the investigator is selected. If organization of a coordinating committee and/or selection of coordinating investigator(s) are to be utilized in multicentre trials, their organization and/or selection are the sponsor’s responsibility.
Before entering an agreement with an investigator/institution to conduct a trial, the sponsor should provide the investigator(s)/institution(s) with the protocol and an up-to-date Investigator’s Brochure, and should provide sufficient time for the investigator/institution to review the protocol and the information provided.
The sponsor should obtain the investigator’s/institution’s agreement:
a. to conduct the trial in compliance with GCP, with the applicable regulatory requirement(s) , and with the protocol agreed to by the sponsor and given approval/favourable opinion by the institutional review board/independent ethics committee (IRB/IEC);
b. to comply with procedures for data recording/reporting;
c. to permit monitoring, auditing and inspection and
d. to retain the trial related essential documents until the sponsor informs the investigator/institution these documents are no longer needed .
Allocation of Duties and Functions
Prior to initiating a trial, the sponsor should define, establish, and allocate all trial-related duties and functions.
Compensation to Subjects and Investigators
If required by the applicable regulatory requirement(s), the sponsor should provide insurance or should indemnify (legal and financial coverage) the investigator/the institution against claims arising from the trial, except for claims that arise from malpractice and/or negligence.
The sponsor’s policies and procedures should address the costs of treatment of trial subjects in the event of trial-related injuries in accordance with the applicable regulatory requirement(s).
When trial subjects receive compensation, the method and manner of compensation should comply with applicable regulatory requirement(s).
Financing:
The financial aspects of the trial should be documented in an agreement between the sponsor and the investigator/institution.
Notification/ Authority(ies)Submission to Regulatory
Before initiating the clinical trial(s), the sponsor (or the sponsor and the investigator, if required by the applicable regulatory requirement(s)) should submit any required application(s) to the appropriate authority(ies) for review, acceptance, and/or permission (as required by the applicable regulatory requirement(s))to begin the trial(s). Any notification/submission should be dated and contain sufficient information to identify the protocol.
Confirmation of Review by IRB/IEC
The sponsor should obtain from the investigator/institution:
a. The name and address of the investigator’s/institution’s IRB/IEC.
b. A statement obtained from the IRB/IEC that it is organized and operates according to GCP and the applicable laws and regulations.
c. Documented IRB/IEC approval/favourable opinion and, if requested by the sponsor, a current copy of protocol, written informed consent form(s) and any other written information to be provided to subjects, subject recruiting procedures, and documents related to payments and compensation available to the subjects, and any other documents that the IRB/IEC may have requested.
Information on Investigational Product(s)
When planning trials, the sponsor should ensure that sufficient safety and efficacy data from nonclinical studies and/or clinical trials are available to support human exposure by the route, at the dosages, for the duration, and in the trial population to be studied.
Manufacturing, Packaging, Labelling, and Coding Investigational Product(s)
The sponsor should ensure that the investigational product(s) (including active comparator(s) and placebo, if applicable) is characterized as appropriate to the stage of development of the product(s), is manufactured in accordance with any applicable
GMP, and is coded and labelled in a manner that protects the blinding, if applicable. In addition, the labelling should comply with applicable regulatory requirement(s).
The sponsor should determine, for the investigational product(s), acceptable storage temperatures, storage conditions (e.g., protection from light), storage times, reconstitution fluids and procedures, and devices for product infusion, if any. The sponsor should inform all involved parties (e.g., monitors, investigators, pharmacists, storage managers) of these determinations.
The investigational product(s) should be packaged to prevent contamination and unacceptable deterioration during transport and storage.
In blinded trials, the coding system for the investigational product(s) should include a mechanism that permits rapid identification of the product(s) in case of a medical emergency, but does not permit undetectable breaks of the blinding.
If significant formulation changes are made in the investigational or comparator product(s) during the course of clinical development, the results of any additional studies of the formulated product(s) (e.g., stability, dissolution rate, bioavailability) needed to assess whether these changes would significantly alter the pharmacokinetic profile of the product should be available prior to the use of the new formulation in clinical trials.
Supplying and Handling Investigational Product(s)
The sponsor is responsible for supplying the investigator(s)/institution(s) with the investigational product(s).
The sponsor should not supply an investigator/institution with the investigational product(s) until the sponsor obtains all required documentation (e.g., approval/favourable opinion from IRB/IEC and regulatory authority(ies)).
The sponsor should:
a. Ensure timely delivery of investigational product(s) to the investigator(s).
b. Maintain records that document shipment, receipt, disposition, return, and destruction of the investigational product(s).
c. Maintain a system for retrieving investigational products and documenting this retrieval (e.g., for deficient product recall, reclaim after trial completion, expired product reclaim).
d. Maintain a system for the position of unused investigational product(s) and for the documentation of this disposition.
The sponsor should:
a. Take steps to ensure that the investigational product(s) are stable over the period of use.
b. Maintain sufficient quantities of the investigational product(s) used in the trials to reconfirm specifications, should this become necessary, and maintain records of batch sample analyses and characteristics. To the extent stability permits, samples should be retained either until the analyses of the trial data are complete or as required by the applicable regulatory requirement(s), whichever represents the longer retention period.
Record Access
The sponsor should ensure that it is specified in the protocol or other written agreement that the investigator(s)/institution(s) provide direct access to source data/documents for trial-related monitoring, audits, IRB/IEC review, and regulatory inspection.
Safety Information
The sponsor should promptly notify all concerned investigator(s)/institution(s) and the regulatory authority(ies) of findings that could affect adversely the safety of subjects, impact the conduct of the trial, or alter the IRB/IEC’s approval/favourable opinion to continue the trial.
Selection and Qualifications of Monitors
a. Monitors should be appointed by the sponsor.
b. Monitors should be appropriately trained, and should have the scientific and/or clinical knowledge needed to monitor the trial adequately. A monitor’s qualifications should be documented.
c. Monitors should be thoroughly familiar with the investigational product(s), the protocol, written informed consent form and any other written information to be provided to subjects, the sponsor’s SOPs, GCP, and the applicable regulatory requirement(s).
Extent and Nature of Monitoring
The sponsor should ensure that the trials are adequately monitored. The sponsor should determine the appropriate extent and nature of monitoring. The determination of the extent and nature of monitoring should be based on considerations such as the objective, purpose, design, complexity, blinding, size, and endpoints of the trial. In general there is a need for on-site monitoring, before, during, and after the trial; however in exceptional circumstances the sponsor may determine that central monitoring in conjunction with procedures such as investigators’ training and meetings, and extensive written guidance can assure appropriate conduct of the trial in accordance with GCP
Audits:Sponsor should perform regular audit duringClinical trial.
Auditing Procedures
a. The sponsor should ensure that the auditing of clinical trials/systems is conducted in accordance with the sponsor’s written procedures on what to audit, how to audit, the frequency of audits, and the form and content of audit reports.
b. The sponsor’s audit plan and procedures for a trial audit should be guided by the importance of the trial to submissions to regulatory authorities, the number of subjects in the trial, the type and complexity of the trial, the level of risks to the trial subjects, and any identified problem(s).
c. The observations and findings of the auditor(s) should be documented.
d. To preserve the independence and value of the audit function, the regulatory authority(ies) should not routinely request the audit reports. Regulatory authority(ies) may seek access to an audit report on a case by case basis when evidence of serious GCP non-compliance exists, or in the course of legal proceedings.
e. When required by applicable law or regulation, the sponsor should provide an audit certificate.
Noncompliance
Noncompliance with the protocol, SOPs, GCP, and/or applicable regulatory requirement(s) by an investigator/institution, or by member(s) of the sponsor’s staff should lead to prompt action by the sponsor to secure compliance.
If the monitoring and/or auditing identifies serious and/or persistent noncompliance on the part of an investigator/institution, the sponsor should terminate the investigator’s/institution’s participation in the trial. When an investigator’s/institution’s participation is terminated because of noncompliance, the sponsor should notify promptly the regulatory authority(ies).
Answer:The general principles of the FDA guidance on the choice of control groups in clinical trials as follows:
· Its ability to minimize bias
· Ethical and practical issues associated with its use
· Its usefulness and the quality of inference in particular situations
· Modifications of study design or combinations with other controls that can resolve ethical, practical, or inferential concerns.
Although this guidance is focused primarily on clinical trials intended to assess the efficacy of a treatment, many of the considerations discussed also apply to the assessment of specific safety hypotheses and to safety or efficacy comparisons of two treatments.
Question20: What are general principles of the FDA guidance on the use of computerized systems in clinical trials?
Following are general guidance on the use of computerized system in clinical trials:
Each study protocol should identify at which steps a computerized system will be used to create, modify, maintain, archive, retrieve, or transmit data.
For each study, documentation should identify what software and, if known, what hardware is to be used in computerized systems that create, modify, maintain, archive, retrieve, or transmit data. This documentation should be retained as part of study records.
Source documents should be retained to enable a reconstruction and evaluation of the trial.
When original observations are entered directly into a computerized system, the electronic record is the source document.
The design of a computerized system should ensure that all applicable regulatory requirements for record keeping and record retention in clinical trials are met with the same degree of confidence as is provided with paper systems.
Clinical investigators should retain either the original or a certified copy of all source documents sent to a sponsor or contract research organization, including query resolution correspondence.
Any change to a record required to be maintained should not obscure the original information. The record should clearly indicate that a change was made and clearly provide a means to locate and read the prior information.
Changes to data that are stored on electronic media will always require an audit trail. Documentation should include who made the changes, when, and why they were made.
The FDA may inspect all records that are intended to support submissions to the Agency, regardless of how they were created or maintained.
Data should be retrievable in such a fashion that all information regarding each individual subject in a study is attributable to that subject.
Computerized systems should be designed: (1) So that all requirements assigned to these systems in a study protocol are satisfied (e.g., data are recorded in metric units, requirements that the study be blinded); and, (2) to preclude errors in data creation, modification, maintenance, archiving, retrieval, or transmission.
Security measures should be in place to prevent unauthorized access to the data and to the computerized system.
Standard Operating Procedures (SOPs) pertinent to the use of the computerized system should be available on site.
Question19: Please, list a CRA’s responsibilities in finalizing the study?
Answer: A CRA must be at the site to do a closeout visit. It would be extremely unusual to try to close out a site without being there in person. Following are the list of CRA responsibilities in finalizing the study:
1. The CRA should make sure that all the case report forms, as well as any corrections or query forms, are complete, in order and ready for storage.
2. If there are still study drug supplies at the site, the CRA should complete a final inventory at the closeout visit. The study drug should then be packaged for return to the sponsor, according to company policy. A copy of the drug inventory form should be placed in the investigator’s study file.
3. The CRA must thoroughly check the investigator’s study document file at this visit. It is wise to use a checklist to ensure that noting is overlooked. All documents must be present, including appropriate re-approvals and correspondence form the IRB. If there were protocol amendments during the study, or amendments to the informed consent form, all versions should be in the file, including their dates of use. Informed consent forms for each subject must be present. The CRA should double-check to be sure they were all signed and dated appropriately. There should be documented for any protocol variations, whether they were previously approved or not. The investigator brochure should be available on or with the file. If any documents are missing from this file, the CRA should help the investigative site to obtain copies.
4. The CRA should verify that Investigator’s final report to the sponsor and the IRB were done, collect copies for the sponsor, if appropriate, and ensure that the reports are in the investigator study file. This report should include an enrollment summary, including the number of subjects entered, those who completed those who dropped out and their reasons for dropping out. It will also include information about adverse events and any other information relative to the trial at that site. The investigator will also make a final report to the IRB. It will contain the information above, in addition to any other information specifically requested by the IRB.The investigator must also notify the institution that the study is complete, if appropriate.
5. Since this is probably the last visit the CRA will make the investigative site for the trial, any outstanding business or issues should be resolved before the study closeout is complete. Any loose ends should be resolved and taken care of before the site is completely closed. The CRA should verify that all appropriate grant monies have been paid or requested. Be sure that the amounts are in agreement between the investigator and the sponsor. If there are unused study materials at the investigative site (case report forms, unused laboratory kits, etc.), they should be returned or disposed of according to the sponsor’s direction. Any outstanding issues from previous visits, or issues that arose during sponsor review, should be resolved before the study is closed out at the investigative site. If not documented elsewhere, a note detailing the resolution should be put in the investigator’s study file.
6. The CRA should discuss record retention with the investigator. Not only do the records need to be stored and maintained, but also there must be a record of where they are stored. According to the regulations, records must be kept for two years after the New Drug Application (NDA) is approved for marketing, or, if an NDA is not filed or disapproved, for two years after the investigation is discontinued and the FDA notified. However, most sponsors expect the investigator to retain all study records until notified by the sponsor that they may be disposed of; this will usually be in the contract that the investigator signed before starting the study. The CRA must be sure that the investigator and site personnel are aware of and understand the retention period
7. The CRA must complete a visit report after this site, as for any other visit. Many companies have a special visit report for closeout visit. This report documents that the study was officially closed. In the final report, the CRA should verify that everything was checked, found complete and prepared for storage. If there were any outstanding issues from previous visits, the resolution of those issues should be documented in this visit report. The CRA should be sure that the report is clear and does not leave any unresolved loose ends.
Study Termination Checklist
In-house
Notify regulatory department when all patients are off drug and study is terminated
Send randomization sheets to investigators, if appropriate (only after all study documents are in-house)
Send clinical data and statistical summary to investigators, if appropriate
Prepare final study reports
Field
All CRFs collected, corrected and in-house
No outstanding data for serious adverse events, deaths, or pregnancies
Drug collected, inventoried and returned to sponsor
Investigator files complete and investigator instructed regarding storage
Drug reconciled from inventory and shipping invoices
Investigator briefed on procedure if notified of FDA audit
Question18: Please list all of the important things to consider regarding volunteer recruitment. For example, you should consider advertisement, incentives, gender of candidates etc?
Answer :In order to get a new drug approved for market, a pharmaceutical company typically has to conduct trials involving more than 3,000 patients. Recruiting an adequate number of patients to satisfy the FDA is one of the biggest hurdles a pharmaceutical company faces when bringing a new drug to market. Poor patient recruitment is the number one reason that trials fail or are delayed
Following are the important things to consider regarding volunteer recruitment:
1. Right Estimation of subjects required by the Trial:
One of the most important pre-study activities a CRA has is to help sites accurately estimate the number of subjects that they can reasonably expect to enroll in each trial. Sponsor companies may recruit the right sites, but these sites may have over-estimated their potential enrollment. Over-estimating enrollment is a serious mistake for the investigator. When a site estimates its ability to participate, the project team counts on it to produce to that level. If the site does not, then the project team looks bad in front of those higher-ups at the company to whom they report.
2. Incentives to Research subject:
There are a number of ways that a site can encourage patients to remain in a study until the end. Any and all efforts to treat patients as special will go a long way to achieving this goal. Here are some other practical tips: The stipend for the study should cover a patient’s out-of-pocket expenses and perhaps provide a small payment for the patient’s time. A typical stipend may pay for $15 to $25 per office visit. Although this isn’t much, for some people it still can provide an extra financial incentive for enrolling in a trial and completing all study visits.
The site should ensure that volunteers’ transportation needs are met. This may involve paying for taxis or even operating a van to transport elderly patients to and from the office. Some volunteers may not own cars and must rely on public transportation; a site should be aware of this and take steps to provide the necessary transportation or cover the associated expense.
If a protocol requires the enrollment of women volunteers, a site may need to provide some type of on-site day care. This is particularly true if the protocol will require the patient to stay in the office for an extended period. Even if the visits are short, a site needs to provide appropriate reading or play materials in the waiting room for the children.
3. Selecting the Right Sites:
Because of the many difficulties in enrolling patients, sponsors place a premium on selecting sites that have a good track record of filling their studies. The site that excels at patient recruitment {and also provides good quality data) can be assured that it will get repeat business from sponsors and that its clinical research business will grow. Sponsors are increasingly looking for sites that demonstrate they can enroll a diverse range of patients. The FDA is putting pressure on sponsors to test their investigational therapies on the full range of patients who will eventually be using the drug (if it is approved for marketing). As a result, sponsors need to recruit different ethnic groups, men and women, and often people of all ages. The site that fully enrolls its studies, and demonstrates that it can recruit diverse patient groups as well, will quickly win favor with sponsors.
4. Patient Recruitment via Advertisement:
In recent years, it has become more common for investigators to use radio and newspaper ads to enhance patient recruitment. The fact that sponsors are willing to pay for this type of expensive advertising exemplifies the importance they are placing on accelerating the clinical development of their new drugs.
A few sponsors are now taking their patient-recruitment efforts a step further and hiring advertising agencies to develop television ads to support their sites. Again, the television ad is developed in a flexible manner so it can be easily adapted for local use. When a sponsor employs a patient recruitment firm to do mass marketing, the site must make sure that it interfaces appropriately with the marketing firm.
The downside to advertising in general media outlets is that often most of the people who respond don’t qualify for the study. A well-placed radio or television spot may generate 100 calls to be screened, but only one or two patients eligible for the study. If this happens, the site incurs significant expense answering the calls and bringing prospective volunteers in for screening visits. In order to be cost-effective, radio, newspaper and television ads need to communicate, as much as possible, the specific therapeutic category involved, since this will help reduce the number of inappropriate calls.
In order to make the best use of advertising dollars, a site should track all patient inquiries and determine how the responders heard about the trial. The tracking will help a site evaluate the effectiveness of advertising in different mediums and how effective advertising can be for different types of studies.
A relatively new avenue for reaching patients is the Internet. The Internet has become a popular resource for people with chronic illnesses searching for medical information. Advertising on the Internet is also much less expensive than radio, news- paper or television advertising. However, it is not likely to generate the same volume of inquiries as radio, newspaper or television ads. Posting information about your research on the Internet should be seen as a way to supplement your regular patient-recruitment efforts.
5. Prompt Scheduling of appointments:
A patient calling with a complaint relevant to the trial can then be immediately scheduled for a visit. This prompt scheduling is important for two reasons. First, it provides the patient with preferred treatment, and this may encourage the person to volunteer for the trial. Second, it may be required as part of the protocol. For example, a protocol may require that patients be enrolled into the study within 24 hours of the onset of lumbosacral pain. In that case, the receptionist needs to immediately schedule an appointment for anyone calling with a complaint about lower back pain.
Question17: What are some of the important points that should be considered during study Initiation?
1)Professionalism
Prefessionalism is the first thing that is expected from a CRA in relation to study monitoring.It is very important for CRA to look and act professional.CRAs can get off to a bad start because of the way they work and dress. The CRA should wear appropriate business attire and should always arrive at the site on time or a little early. The CRA must remember that he or she is an official representative of the sponsor and should always behave in an appropriate business-like manner.
Monitoring requires a lot of unsupervised time “on the road .There are many temptations when traveling that can distract a CRA from work – shopping, museums, television or the latest bestseller but CRA should act in a professional manner and should not let hum self get distracted.
2) Excellent Communication Skills:
A CRA must determine how to integrate telephone, email, fax and regular mail communications into a monitoring strategy. This will differ for different programs and sites. It will depend on the technologies available, sponsor and site Standard Operating Procedures (SOPs) and personal preference, both at the site and at the sponsor company. In monitoring, like any business, many problems can be traced back to a lack of communication, inappropriate communication and/or unclear communication. A good communication strategy should have a high priority in CRA monitoring plan.
3) Good Observation Skills:
There are a number of general things the CRA will want to be aware of when monitoring a site, including interpersonal relationships, the stability of the staff, organization, how site personnel manage their time, and an overall impression and feeling about the site. The reason for this is that the atmosphere at a site affects the study. The better it is, and the smoother things run, the better the study will go.
It is important for a CRA to be observant. Do people get long well with each other? Do they work together? Are there obvious antagonisms, one-upmanship, etc? If one person is very busy, do others help out? If there are problems, the CRA may need to work around them in order to achieve the monitoring objectives.
4) Problem Solving Ability:
Another CRA responsibility is problem solving. Things rarely go exactly as planned, and clinical trials are no exception. The CRA must be prepared far a variety of potential problems such as enrollment difficulties, personnel turnover, waning interest in the study by site personnel, poor conduct of the study and protocol violations. Experience, knowledge and good common sense are CRA best tools for problem solving. If there are problems with site management, the CRA may have to monitor more often to ensure that the study is run properly and that things get done in timely manner.
5)Time Management:
A CRA will need to develop an overall “hands on” monitoring strategy for site visits. In general, it is best to start with the most important activities, or at least the ones that must be done at each visit. This will ensure that is time runs short and everything cannot be completed, at least the most important things will have been reviewed.
It is expected from a CRA to make monitoring plan consistsing of the following activities, done in the order listed:
Serious adverse event review
Informed consent review
Checking protocol adherence
Case report form review and source document review
Queries and error correction
Investigational product review and accountability
Review of laboratory samples
Study document file review
Serious Adverse Event Review
One of the first things a CRA should do at each monitoring visit is ask the investigator and coordinator if there have been any serious adverse events since the last visit, and if there have been, if they were reported to the sponsor. e CRA should examine the information available about the events, including a review of the patient chart and any supporting documentations. If additional information is available that has not gone to the sponsor, the CRA can gather it and ensure that it is submitted to the appropriate person at the sponsor in a timely manner.
informed Consent Review
At each visit, the CRA should check the informed consents for each new subject enrolled since the last visit. Informed consent forms should be signed and dated by the last visit.
Checking Protocol Adherence
Checking protocol adherence it something the CRA should check when monitoring each subject’s dataTo ensure adherence, the CRA will want to check the following items:
Subject eligibility. Did the subject meet all the inclusion and exclusion criteria?
Randomization. Was the subject randomized to the correct subject number and did he or she receive the appropriate packages for investigational drug?
Protocol activities. Were the correct activities done for or by the subject at each visit?
Visit schedule and windows. The visit window is the number of days around the actual projected visit date when the subject can be seen. The window is usually the date plus and minus a number of days.
Case report form review
When review the case report form for a subject, the first thing to do is check each single page. The CRA should check for completeness, ensuring that each item has been completed and each blank is filled in. Are the forms legible?
The CRA should think about what appears in the forms, and whether or not it makes sense, given the subject condition and the study activities. If something does not make sense, the CRA should discuss it with the study coordinator and/or investigator
Source document review
Source document review, sometimes called source document verification, involves checking the data recorded in the case report forms against data found in available source documents, including the patient chart, laboratory reports and other supporting documents.. A source document is any document where the data are first recorded.
The purpose of source documentation is twofold: first, to verify that the subject exist and, second, to verify that data in the CRF are consistent with the information found in the source documents, which verifies the integrity of the data.
Errors, queries and corrections
Perhaps the most important errors a CRA might find are those that result in protocol violations. These include such things as a subject not meeting the inclusion/exclusion criteria, a wrong diagnosis, a subject taking disallowed medications, problems with visit windows and others.
The CRA should note them in the corrections/questions log and discuss them with the study coordinator. When they are resolved, the coordinator should make the necessary corrections to the case report forms; CRAs do not make the corrections. Corrections are made by drawing a line through the incorrect entry, making the correct entry and dating and initialing it
6) Confidentiality
During all monitoring activities, the CRA must be attentive to confidentiality. No study record, other than the consent form should identify the subject. The CRA has an obligation to help protect the confidentiality of all study subjects. The study documents are also confidential. During site visits, sometimes CRAs have seen competitor’s protocols lying around unprotected. All one needs to see is the protocol cover page to know the name of the drug and phase of development. The CRA should periodically remind the investigator and coordinator of the confidentiality of these documents, and ensure that they are kept in a secure location.
It is also the responsibility of a CRA to make monitoring visit report at the end of each visit. The purpose of the monitoring visit report is to document the findings from the monitoring visit. The CRA should use this from to summarize what was done at the investigative site, including CRFs gathers for shipment to the sponsor. This is also where problems must be documented, including what was done to solve them, or to make recommendations of action items for the next visit.
Question2: Please list what is to be expected of a CRA in relation to study monitoring?
Answer:
Study Initiation:
Once a site has received IRB approval and the routing process has been completed, the sponsor will arrange the study initiation visit. With exceptions, this is when most sites receive study drug and case report forms. Most sponsors will not send drug to the site without at least provisional IRB approval.
Study initiation is an important time point in any study. This is the sponsor chance to get all the players at the site together for training on the study requirements and it serves as a signal that the project is now ready to get underway. It is important to include as many staff members as possible:
Principal investigator
Sub-investigator
Coordinator
Technologist responsible for laboratory testing
Pharmacists
It is important that each individual clearly understands their role and responsibility in the project .Involving them in the project at the time of initiation by making them aware that they are part of the team and it is important for the study that they give their best.
The study initiation visit is another chance to show off the quality of the study site to the sponsor. These studies are best done with the Physicians who have a busy patient schedule so it can be a challenge to get the initiation on their schedule. Schedule the time with the Physicians for the lunch hour and provide some sandwiches, a treat appreciated by the Physicians as well as the sponsor staff.
Ensuring that the arrangements for storing and issuing the study drug and maintaining blindness (if appropriate) are in place. The storage space for the study drug must be secure and envoirmental appropriate. Ensure that a log of envoi mental conditions (example: temperature and humidity readings) is maintained. The pharmacy is also a key in the randomisation and blinding process and therefore in the smooth running of the trial.
Study Initiation Checklist
In-house
Send study package(s) to field monitors (Protocol, Brochures, Consents, 1572, contracts/agreement letters, etc.)
Submit appropriate documents to Regulatory Affairs and/or place in study file
Submit initial grant payment request, if appropriate
Send laboratory normal ranges to Biostatistician/Data Management
Ship clinical supplies (notify field monitor (CRA) when drug is shipped)
Field
Conduct site initiation visits
Confirm receipt of clinical supplies with each site
Review protocol requirements
Review sponsor policy on CRF completion and correction
Confirm presence of all required documents
Ensure establishment of study files
Establish monitoring visit frequency and communicate to site
Question15: Please create a checklist for a pre-investigation visit for a phase II clinical trial on X-micine: a new anti-viral compound that reduces the death rate from S. A. R. S.?
Answer:
Prestudy Activities Checklist
Following is the checklist for a pre- investigation for a Phase II clinical trial on X- micine(a new anti-viral compound that reduces the death rate from S. A. R. S.)
Site Evaluation Visit by Sponsor/Sponsor Rep
Review protocol with principal investigator
Tour research site, hospital, laboratory, pharmacy as appropriate
Organize Site Initiation Visit (document training)
Principal investigator
Sub-investigators
Clinical coordinators
Appropriate staff
Clinical research pharmacist
Compiling Prestudy Documents
Site Survey Form
Confidentiality Agreement:Must be signed by the principal investigator before study protocol can be sent.
FDA Form 1572:Must be signed by principal investigator. Summarizes the FDA requirements for participating in a clinical study. All sub-investigators must be listed.
Curriculum Vitae(CV): Required of the principal investigator and all sub-investigators. In addition CVs of the clinical research coordinator and lab director are required when appropriate
Financial Disclosures: Required of the principal investigator and all sub-investigators
Laboratory Certification: A copy of local laboratory licenses and the normal laboratory values for the laboratory to be used must be kept on file.
Signed Protocol Agreement: Must be signed by the principal investigator.
Study Contract/Budget: Between the sponsor, principal investigator, and institutions where research will be conducted.
IRB Informed Consent Form Approval
IRB protocol approval letter
IRB informed consent form approval letter
IRB patient information / advertising approval letter
Approved HIPPA Form
IRB Membership List
Investigator’s Brochure
Test Article Inventory / Accountability Record
Test Article Storage Area Temperature Log
Case Report Forms
Adverse / Serious Adverse Event Forms
Additional documents will be needed as study progresses. Examples include:
Amendments to study protocol
Executed informed consents
Diagnostic test results
Test article inventory / shipping invoices / packing slips
