Informed Cosent

22. March 2010 by harshit.

Millions of volunteers participate in government- and industry-sponsored clinical trials each year. Prior to agreeing to participate, every volunteer has the right to know and understand what will happen during a clinical trial. This is called informed consent and it is a process that can help you decide whether or not participating in a trial is right for you.

Before participating, the volunteer must understand:

Your bill of rights
What you should know
What questions you should ask
Take time to understand
Volunteering for a clinical trial

Your bill of rights

If you have given consent to participate in a clinical trial, or if you have given consent on behalf of another person, you both are entitled to the following rights:

To be told the purpose of the clinical trial
To be told about all the risks, side effects, or discomforts that might be reasonably expected
To be told of any benefits that can be reasonably expected
To be told what will happen in the study and whether any procedures, drugs, or devices are different than those that are used in standard medical treatment
To be told about all options available to you and how they are better or worse than being in a clinical trial
To be allowed to ask any questions about the trial prior to consenting and/or at any time during the course of the trial
To be allowed ample time, without pressure, to decide whether or not to consent to participate
To refuse to participate, for any reason, before and after the trial has started
To receive a signed and dated copy of the informed consent form
To be told of any medical treatments available if complications occur during the trial

What you should know

When you give written consent to participate in a clinical trial, you are acknowledging that you understand and accept all aspects of the research study—including any risks or benefits involved. However, informed consent is not strictly about signing a document. It is a process that involves ongoing conversations between the research staff and you before, and even after, you decide to become a study volunteer.

To begin, the research staff is obligated to discuss all the pertinent information about the trial—its purpose, the procedures involved, the potential risks and benefits—with you. It is your responsibility to ask questions if there is something you do not understand.

If you do not understand any part of the process, ask the researcher to repeat the information or to explain it in another way, using everyday words. If English is not your first language, inform the researcher that you are not comfortable speaking about a clinical trial in English. Upon request, research centers can and should produce documents that explain every aspect of the study and study personnel should be able to explain the information to you in your preferred language. If this is not possible, you should not participate in the study.

It is the responsibility of the research staff to help you understand the information they provide you and to give you enough time to ask any additional questions you may have. In some instances, this may not be possible to accomplish in a single visit, therefore it is essential to take the time you need to make an informed decision. You may discover important concerns that you did not think about during the first visit.

What questions you should ask

The following represents a sample list of questions that you should ask during the informed consent process:

About the clinical trial

What is the main purpose of the study?
Why is this study important to me?
What are the chances that this drug will work?
What kinds of risks are involved?
How much of my time will this take?
Does the study involve a placebo or a treatment already on the market?
About your care

What kinds of tests will be done? Will they hurt? If so, for how long?
How will the tests in the study compare to tests I would have outside the study?
Will I be able to continue to see my own doctor during the study?
Will I be able to continue to take my regular medications during the study?
If I have side effects, can they be treated during the study?
About personal matters

Who will review information collected about me during the trial?
What happens if I decide to quit the study?
Can the investigator take me out of the study even if I want to continue?
About compensation and costs

Do I have to pay for any part of the study? If so, will insurance cover these costs?
Take time to understand

A recent CenterWatch survey of 590 study volunteers offers insight into the informed consent process and whether or not it is working to help volunteers understand their roles and responsibilities. Some key takeaways from the study are:

Nearly 96% of volunteers said they received the informed consent form and 86% said they read the form completely.
The vast majority of volunteers said they understood the expectations of the study, including additional risks and their ability to withdraw at any time.
More than three-quarters understood that they could contact someone outside the study if they had additional questions about their rights during the trial.
More than half the volunteers were unaware that neither their doctor nor they would know what medication they would receive during the study; more than two-thirds understood that they could receive a placebo in the trial.
Nine out of 10 volunteers said that the information received prior to the trial matched their actual experience during the trial.
Approximately 75% of the volunteers indicated that the main reason for participating in a study was to help themselves or others and to advance science.
Research studies are very involved so it is important to learn as much as possible about the study you may participate in before you consent. The U.S. Food and Drug Administration (FDA) guidelines state that study volunteers should understand the risks they’re taking, which may mean spending additional time with the research staff to make sure you get the information you need. If you want to know details, such as any documented side effects of a particular drug observed in earlier clinical trials, you must ask for that information as well as any other information you may want to know.

The decision to participate in a clinical trial is a personal one and one that you are entitled to make freely, without influence or coercion. Being properly informed so that you fully understand the responsibilities of becoming a study volunteer is the best way to ensure that you are making the right decision for you.

Volunteering for a clinical trial

The participation is voluntary and the paticipant can withdraw the consent at any time during the trial with or without informing the cause.

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Data Capture Methods

22. February 2010 by harshit.

Definition of Clinical Data Capture

Collection of clinically significant data by the Investigator/s for clinical trials on behalf of the Sponsor in a sequential manner (per protocol) to process the same and generate reports at a later stage for submissions to regulatory authorities for various purposes
• Procedures for gathering and recording data from or related to subjects in the study
• Paper based OR Electronic Data Capture (EDC)
• Promise of increased efficiency has led to increasing movement toward  implementation of the electronic medical record and to computerized automation in general

Paper Based Data Capture
• Most widely used form of data capture
• Traditional paper Case Report Forms (CRFs)
• Manual entry by site personnel on three-part NCR paper CRFs
• 1 copy retained at investigator site, 2 copies sent to Sponsor or CRO’s Data Management department

Paper Based Data Capture
• Easy to enter data
• Requires simple training
• Logistically patient’s bedside may not be the right place for a computer to enter data.

Draw Backs of Paper CRF
• Storage problem
• Time consuming
• Cost of printing and distribution/ Imaging
• Lack of real-time reporting
• Increasing pressure on sponsors to get drugs into market faster
• Confidentiality and Security

Electronic Data Capture (EDC)
• Capability to collect data electronically
• Also known as Remote Data Entry (RDE)
• Online and offline
• Becoming more common than paper technology

Definition of EDC by the Clinical Data Interchange Standards Consortium (CDISC):
• “Collecting or acquiring data as a permanent electronic record with or without a human interface (eg., using data collection systems or applications that are modem-based, web-based, optical mark/character recognition, or involve audio text, interactive voice response, graphical interfaces, clinical laboratory interfaces, or touch screens). Note: ‘Permanent’ in the context of these definitions implies that any changes made to the electronic data are recorded via an audit trail.”

EDC Tools
• Internet
• Interactive Voice Response (IVR)
• Pen Tablet
• Personal Digital Assistant
• Fax
• Image Recognition Technology (OCR & OMR)
• eCRF

Internet
• Programs and databases located on centralized website
• Data keyed in with access to a browser
• Online
• Real-time reporting possible
• Good solution for small providers who cannot afford software costs

Interactive Voice Response (IVR)
• Interactive speech or touch-pad menu-driven system that takes the caller through a series of prompts
• Responses entered through a telephone keypad
• Real-time reports generated
• Almost maintenance free
• Limited interface
• Typically used in select areas such as patient randomization, adverse event reporting, drug supply management, tracking visit milestones, assisting with study startup or collecting subject diary information

Pen Tablet
• Reduce paper costs by allowing full-size form filling, signature, and simultaneous form inking Ex: ClipGem Pen Tablet
• Users affix a paper form under the clip and sign each individual signature field
• User’s signature and biometric data captured, software binds it to the electronic copy of the document in real time, and the inking tip of the pen makes a paper record
• Powered by computer’s serial or USB port, hence no batteries or bulky wall transformers  needed

Personal Digital Assistant (PDA)
• Replace paper-based subject diaries
• Stores data until transfer to study database
• Hotsyncing to a computer where the data is downloaded and stored
• Typically operates in offline mode
• Eliminates data entry

Fax
• Software scans faxed patient forms and faxes back a report, eliminating the need for data entry at the clinic level

Limitations:
a) Confidentiality
b) Maintenance and monitoring
c) Availability of clerical staff to verify submissions
d) Slow turn around time

Image Recognition Technology
• Image-recognition systems, including optical character recognition and optical mark recognition, provide a means of capturing data from printed sources
• Data on paper chart à Scan à OMR/OCR software àEMR

Optical Character Recognition (OCR) technology
• Translation of printed text on each page to electronic text documents
• OCR software converts scanned image to machine-readable and editable text
• Equivalent to keying in text by hand
• Less costly and faster compared to manual keying in
• Scanning preprinted paper forms to convert marks in checkboxes, text printed in block form, and barcodes into machine readable text
• Questionnaire format commonly used in post-marketing trials
• Fast and time saving

Representation of process of using a flatbed scanner and OMR or OCR software. A flatbed scanner with a sheet feeder is the rate-limiting step in the conversion of printed documents and forms to machine-readable data.

eCRF
• Direct entry into eCRFs that have some form of in-built real-time data validation checks. Updates to data done electronically
• Transmission of data to sponsor accelerated
• Faster and more active management of the data gathering and processing workflow
• Ensures “cleaner data faster”
• User interface to be designed with user characteristics in mind
• Validation inputs to be taken into account during initial designing
• Integration of EDC with other corporate systems to be included in designs from the start, as well as information messaging and workflows

Advantages of eCRF Over Paper CRF
• Automated data edit checks alert the site to possible errors in data entry
• Faster correction of issues and immediate site education. Hence cost saving
• Immediate viewing by sponsor to review and analyse the data and provide online feedback to the site.
• Shortens time between ‘last patient last visit’ and ‘database lock’

Advantages of eCRF
• Project Manager: access to real-time project metrics
• Clinical Monitoring Staff: less time spent in site visits
• Investigator Sites: less query resolution and less storage issue
• Data Management: eradication of double data entry and faster turn around

Limitations of eCRF
• Resistance to change
• Integration of multiple systems and groups
• Indecision and fear among Sponsors

eSource
• Data directly entered into eCRF without paper source
• Eliminates errors and delays that occur in transcription from source to CRF
• Single data entry

eSource Data
Definition per ICH (International Conference on Harmonization):
   “Source data captured initially into a permanent electronic record. Note: ‘Permanent’ in the context of this definition implies that any changes made to the electronic data are recorded via an audit trail.”
Definition per ICH:
  “All information in original records, certified records, and certified copies of original records of clinical findings; observations; or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in source documents (original records or certified copies).”

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Costs and finances in clinical trials

8. February 2010 by rahul.

India: Hub for clinical research

• Large number of patients
• Faster recruitment
• Highly qualified professionals
• Global quality medical care
• Low trial costs
• Highly developed IT and data collection
• More and more global sponsors are moving to India for clinical trials
• Exponential growth in no. of CTs and the industry

India and clinical research..

Until recently, there were few clinical trials conducted in India by Western pharmaceutical and biotech companies, primarily because of regulatory hurdles. In January 2005 it was recognized that the significant advantages that India offers to multinational companies and the potential and benefits of conducting clinical trials in India, should be utilized. The Government of India upgraded Schedule Y of the Drugs and Cosmetics Act of India, the equivalent of the sections of the Code of Federal regulations applicable to the FDA, to harmonize it with U.S. and International Conference on Harmonization (ICH) standards.

These changes removed a number of regulatory barriers to performing clinical trials in India

• The changes formalized the definition and conduct of clinical trials

• Specified the responsibilities of the sponsor, the investigators, and the Ethics Committees

• Developed guidelines and procedures for importing drugs for clinical trials

• Instituted required compliance with GCP

• Specified the requirements for informed consent

• Defined the structure, content and formats of clinical study reports

• In addition, the Indian Government provided increased protection for intellectual property (IP).

India….Clinical Trial costs                                                                                                                                                             The cost per patient for trials in India is approximately 40 to 60% of the cost in Western nations. More importantly, patient recruitment can be greatly accelerated, and this provides a major advantage in terms of shortening the time to market for a new drug. Based on these many advantages, the number of clinical trials in India is expected to grow exponentially over the next five to ten years. The average cost of running a US-based clinical trial per patient is $5,404 for Phase I, $6,538 for Phase II and $7,635 for Phase III.According to an analysis in 2006, conducting a clinical trial in a lower-cost destination such as India, for example, can cost up to 60 per cent less than in the US. However, while quickly gaining momentum, India’s much hyped clinical research industry is still yet to really take off. Since the introduction of patent protection laws in 2005, the industry has been growing three digits. However, this growth has not been as fast as many have predicted.

While deciding the costs for a clinical trial several factors are taken into consideration by the sponsor

In house costing plus out sourcing costs.
In house costing, all infrastructural expenditure has to be accounted for.
For outsourcing costs: CROs have come to play a crucial role in clinical research. The government plays a crucial role in regulating clinical trial costs. A report by analysts estimated that clinical research in India will be a $1bn (€800,000m) industry by 2010.Although many analysts expect it will be closer to half that

The government initiative.
Indian govt. recently announced a tax exemption on all services carried out by its contract research and clinical trials industry – a saving of 12.24 percent. The decision removes a previous stumbling block that international pharmaceutical sponsors faced when considering contract research organisations (CROs) in India. This is designed to give a boost to this budding market. Cost-savings are a significant draw card for many pharmaceutical companies when deciding to outsource clinical research to countries in emerging markets such as India and Latin America. In the last 10 years, skyrocketing costs of R&D have led to a growth explosion in the clinical services industry as pharma companies scramble to cut costs

Tax exemption…in Clinical Research
It is hoped that this move by the Indian government will give the industry the kick that it needs to live up to expectations. To make India a preferred destination for drug testing.
This includes technical testing and analysis for testing of new drugs, vaccines and herbal remedies, on human participants by a CRO approved to conduct clinical trials by the Drugs Controller General of India. This will attract more clinical trial outsourcing as the pharmaceutical sponsors will heavily benefit on their cash outflows on account of their expenses on CRO fees

CROs and clinical research
CROs are rapidly emerging as important contributors in clinical research Currently; CROs are having to ask sponsors for reimbursement of this service tax and paying it to the government. This relaxation by the govt. has sent positive signals for the growth of the clinical trial industry

The pharma industry…
A biopharmaceutical company discovers, develops, and commercializes therapeutic medicines for the treatment of serious medical conditions. It has therapeutic candidates in clinical trials for the potential treatment of diseases. It has the ability to understand thoroughly the biology of specific disease states, discover potential therapeutic candidates and evaluate product candidates in clinical trials.

How the industry manages costs ?
Financing, budgeting and cost control are essential aspects of clinical trial management
Specifically trained professionals, like CAs, MBAs, etc. are employed by the industry to handle this problem. Responsibilities include estimating, budgeting, forecasting, monitoring, planning, and allocating resource for clinical operations.

The need….
Ability to analyze clinical financial data and prepare management reports and forecasts, including earned value management reports. Effective documentation and communication for interacting with and making an impact on functional teams .Accurate and timely financial budgets, forecasts, actual and variance analyses under tight deadlines. The ability to manage multiple competing priorities

So, Clinical trials are not only a scientific exercise but also involve administrative and financial aspects. Need for focused expertise, innovative processes, and integrated technology. High quality, efficient and cost effective service solutions are needed to address many of the critical financial and administrative issues that affect the clinical trial proces

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Clinical Trials: Need and Ways

27. January 2010 by rahul.

Development of new drugs/medicines/therapeutic modalities revolutionized the practice of medicine. The new medicine discoveries have converted many once fatal or debilitating diseases into almost routine therapeutic exercises. For example today deaths from cardiovascular disease and stroke have decreased by almost 50% or less over the past 30 years. This reduction is due-in part- to the discovery and increased use of antihypertensive, cholesterol synthesis inhibitors and drugs that prevent or dissolve blood clots. As the number of potential medicines produced increases, the problem of whom to test them on grows. There are two main groups: healthy volunteers and volunteer patients (plus rarely non volunteer patients). Studies in healthy normal volunteers can help to find out the safety, tolerability, pharmacokinetics and for some drugs, e.g. anticoagulants and anaesthetic agents, their dynamic effects. Otherwise for most drugs the dynamic effect and thus the therapeutic potential can only be investigated in patients, e.g. drugs for epilepsy or antimicrobials. Introduction of novel agents into both groups poses ethical and scientific problems.

There are four reasons why medical practitioners (or medical trainees) should have grounding in the knowledge and application of tested principles of experimental therapeutics:
1. Optimal selection of a specific dose of a medicine for a specific patient requires a sound backup of good clinical research. To some extent every new administration to a patient is an exercise in experimental therapeutics.
2. Increasingly doctors are personally involved in patient care.
3. Such studies provide an exercise in ethical and logical thinking.
4. Good clinical research alters clinical practice.

Human Experiments Vs Clinical Research
1. Some people are averse to the word ‘experiment’ in relation to man, thinking man to be a guinea pig. That immediately implies a degree of impropriety in what is done.
2. It is better if all who are concern recognize the true meaning of the word, i.e. to ascertain or establish by trial (Oxford English Dictionary), that the benefits of modern medicine derive almost wholly from scientific experimentation and that some risk is inseparable from much medical advances.
3. The moral obligation of all medical practitioners lies in ensuring that in their desire to help patients (the ethical principle of beneficience)                                                                                                                                                                 4.They should never allow themselves to put the individual who has come to seek their help at any disadvantage (the ethical principles of non-maleficence) as the scientist or physician has no right to choose martyrs for society.

Studies involving human subjects fall into two distinct categories
1.Clinical studies: The class of all scientific approaches to evaluate medical disease preventions, diagnostic techniques and treatments using human subjects (either healthy volunteers or volunteer patients or samples obtained from them) essentially as experimental animals.
2. Clinical Trial: It is a subset of those systematic clinical studies that evaluate the new drug(s) in human subject(s) to generate data for discovery and/or verifying the clinical pharmacological (both pharmacokinetic and pharmacodynamic) and/or adverse effect with the objective of determining efficacy and/or safety of the new compound(s).

These clinical studies are done in four phases of drug development, namely Phases 1, 2, 3 and 4. Phase 4 evaluations of marketed medicines in formal clinical trials using the same or similar types of protocols to those used in Phases 1 and 3 are also referred to as clinical trial. A clinical trial is a method for comparing objectively by a prospective studies the results of two or more therapeutic procedures. Until about 30 years ago treatment methods were chosen on the basis of clinical impressions and personal experiences rather than objective testing. As a result many drugs with undoubted effectiveness remain in use without ever having been subjected to a control trial. As per regulatory requirements any new drug is now needed to have been tested in this way before being licensed for general clinical use. A clinical trial aims to compare the response of a test group of patients receiving a new drug treatment (A) with that of a control group receiving another treatment (B).

The proposed trial should be carried out, only after approval of the Drugs Controller General of India (DCGI), as is necessary under the Schedule Y of Drugs and Cosmetics Act,1940. The investigator should also get the approval of Ethical Committee of the Institution before submitting the proposal to DCGI. All the guiding principles should be followed irrespective of whether the drug has been developed in this country or abroad or whether clinical trials have been carried out outside India or not.

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PROJECT MANAGEMENT

25. January 2010 by harshit.

Improving Quality & Efficiency through Efficient
Project Management

The Gartner Research Group (USA) reports that “Close to 30% of projects are never successfully completed, wasting about US$75 billion annually, and a startling 51% of
projects exceed their budget by 189% and deliver only 74% of expected functionality. While these data are astonishing in themselves, the greatest contributor to project failure
can be explained by one factor, namely Poor Project Management.

A project is a sequence of unique, complex and connected activities that are completed to achieve one goal or purpose in a limited timeframe. It is performed by the people and
constrained by resources. It is usually planned, executed and controlled.

A project can be thought of as “a temporary endeavour” or “an organized undertaking” and could be simple like finding a job or buying a house, to more complex like running a
campaign for political office, constructing a building, developing a new product or service, conducting a clinical study, or large like design and manufacture a car or really
huge like putting a man on the moon!

Project Management is about managing projects. It is a dynamic process and is based on accepted principles of management. It is the application of knowledge, skills, tools and techniques to meet the needs and expectations from a project. The goals of project management could be, for example, clinical (e.g. demonstrate safety and efficacy of a
drug and obtain regulatory approval) and business (e.g. finish within time and budget, and make a profit).

Often several concerns are raised about project planning including, “My work is research therefore I can’t plan it” or “How can I commit to a schedule, if I don’t know how it will
work out ” or “I don’t have time to plan –got to get it done!” However, it is important to plan a project. The Project plan is a map and a guide. If there is no map, you are most
likely to get lost. A plan helps you to understand risks and trade-offs. It is the basis for systematic plan modification and a mechanism for efficient communications.

Principles of Project Management

a. Set objectives and work towards them (e.g. achieve the project goal, keep customers happy, keep the team focus on the goal or make sure that team members work well
and everyone shares the load
b. Establish forward-looking control
c. Good decision making

Project Management processes

Various processes are linked in project management, including,
a. Initiation
b. Planning
c. Control and Executing
d. Close out

Primarily it is necessary to decide what is “Expected” from a given project, around which a project plan is built with buffer ranges. Vital signs of a project should be monitored e.g. plan change frequency, on time completion rate, or cost estimate vs. actual costs.

Estimates must be checked against the actual costs. Routine “Checkups” are arranged as early detection allows for speedy and low-cost treatment. Diagnostic tests for areas of
concern must be increased. Limits must be set for acceptable ranges. The project team may be altered when vital signs are unfavorable. A specialist may be brought in when needed!

There are core knowledge areas in Project Management including management of project integration, management of scope, time, cost, quality, human resource, communications,
risk or procurement.

The Project Plans could include plans for Resourcing, Communications, enrolment, monitoring, Site Management, Safety Management, Document Management, Quality
Management, Clinical Trial Material Management, Logistics and Medical Monitoring.
The aim of Project Management is to reduce time and cost and increase quality. Hence the three most critical success factors in any project are Speed, Quality and reduced costs
which impact on schedules, planned results and resources.

Project Time management
a. Activity definition
b. Activity sequencing
c. Activity duration estimation
d.Schedule development
e. Schedule control
f. Identification of Rate limiting steps in a study
i. Long start up timelines (EC)
ii. Clinical trial agreement
iii. Availability of patients
iv. Resource transition
g. Accurate projections at the time of feasibility
h. Importance of Inter-activity logical relationship
i. Plan for the duration of study, closely track
j. Scheduling activities from SSV to SCV (pre-screening to study closeout)
k. Compliance to monitoring and auditing

Project cost management

This includes resource planning, cost estimation, cost budgeting and cost control. For this physical resources needed are identified, cost estimates provided, resources budgeted in the CTA and expenses closely monitored.
Project Quality Management

There has to be quality planning with both QA and QC in place. The Quality policy should have a clearly defined scope with SOPs and regulation in place. Internal QC
monitoring should give trend analysis and have to be enhanced by external audits and inspections. Adherence to protocol, GCP and applicable regulatory guidelines, fulfilment of the Investigator’s Obligations, Monitor Compliance, and timely communications are checked. Regular and corrective training and other proactive steps must be taken to improve Quality of a project.

Project Risk Management
Risk Identification, Risk Analysis (Qualitative and Quantitative), Risk response plan and Risk monitoring and control form the planning of project risk management. Essentially it is all about WHAT COULD GO WRONG. For example, slow product availability,
unexpected SAEs, slow IRB approval, slow recruitment and increased expenses could all pose risks to the project over budget.

A risk management plan would identify & prioritize risks. A Qualitative/ Quantitative analysis is followed by a plan for response to the risk. Monitoring and control are also
planned.

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Pharmacovigilance :

17. January 2010 by harshit.

pharmakon-a drug or medicine
vigilans-watchful or careful

• The monitoring, detection, evaluation and responding to drug safety hazards in humans during pre’marketing development and post-marketing (Shakir and Lezton 2002)
• WHO: The science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem (Edwards 2002)

Ÿ  Safety monitoring and evaluation throughout whole life-cycle of a productŸ   Encompasses non-clinical, clinical, post-marketing safety dataŸ  Evaluation requires a holistic approachŸ  Signals detected during development do not necessarily kill the productWhy pharmacovigilance?

• Limited value of animal experiments in predicting human safety
• Clinical trials are limited in time and number of patients; are ‘artificial’. Patients are selected (adults, no other drugs, no other diseases). Not representative of real-life use.
• Rare or delayed serious reactions are likely to remain unnoticed
• Ethical Requirements
• Legal Requirements
• Assess risk benefit

Functions of pharmacovigilance
(WHO Guidelines, 2000)

• Detection and study of adverse reactions
• Measurement of risk
• Measurement of effectiveness
• Benefit & harm evaluation
• Dissemination of information, education

Ø    Early warning Ø    Rational and safe use of medicines CORPORATE PHARMACOVIGILANCE- SCOPE

• Identify common and rare side effects
• Assess risk benefit Processing and regulatory submission of SAEs
• Processing and regulatory submission of SAEs
• Communications of SAEs reported
• Causality assessment of SAEs reported in any part of world
• Monitoring compliance of SAE processing and reporting
• Generation of PSURs

Rationale for pharmacovigilanceInformation obtained prior to first marketing is inadequate to cover all aspects of drug safety:

•     tests in animals are insufficiently predictive of human safety,
•     in clinical trials patients are selected and limited in number,
•     conditions of use in trials differ from those in clinical practice,
•     duration of trials is limited
•     Information about rare but serious adverse reactions, chronic toxicity, use in special groups (such as children, the elderly or pregnant women) or drug interactions is often not available.
• Prevents Disasters
• Builds up customer confidence
• Ensures Compliance and retention
• Builds brand image

Pharmacovigilance is needed in every country, because there are differences between countries in the occurrence of adverse drug reactions because of differences in:

•   drug production
•   distribution and use (e.g. indications, dose, availability)
•   genetics, diet, traditions of the people
•   pharmaceutical quality and composition (excipients) of locally produced pharmaceutical products
•   the use of non-orthodox drugs (e.g. herbal remedies) which may pose special toxicological problems, when used alone or in combination with other drugs.   

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Adaptive Clinical Trials

17. January 2010 by harshit.

Clinical trial methodology that allows trial design modifications to be made after patients has been enrolled in a study, without compromising the scientific method and integrity of data.

It also Empowers sponsor to response to data collected during the Trial like Modifying sample size, dropping a treatment arm, balancing Treatment assignments using adaptive randomization or simply stopping a study early for success or failure.

Patients randomized to treatment arms based on the response to treatment of previous patients. Real-time safety & efficacy data incorporated into randomization strategy and Play-the-winner: Assignment of patients to treatment arms that resulted in fewer adverse events or better efficacy

Advantages:

Cost reduction: Stopping unsuccessful trials earlier, identifying successful trials sooner, dropping unnecessary treatment arms or     determining effective dose regimes faster

Reduction in lead time between phases, especially II and III:

Reduced time to market

Improved patient safety

Reduced exposure to unsuccessful treatment arms    

Increased access to effective treatment arms

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How ICH-GCP differs from Indian GCP?

11. January 2010 by rahul.

Investigator Qualifications

The Indian GCP (3.3.1) insists that the investigator should be qualified as per the requirement of the Medical Council of Indian (MCI).This means that non-medical scientists e.g. pharmacists who organize the bio-equivalence studies, cannot become investigators.The qualifications of some of the senior investigators were not recognized as the medical institute from where these investigators were not approved by MCI at that time. Even in the medical field, several eminent investigators have medical degrees from UK or US, which are not prescribed by MCI.

Challenges- Investigator Qualifications
Implementation of this provision will require the monitors and auditors to ask the investigators for proof that their qualifications are in line with MCI.This provision can become a major hurdle for sponsors in selecting investigators and needs to be modified in line with ICH-GCP

Investigator and Sponsor’s SOPs
The Indian guideline (3.1.3) mandates that the sponsor and the Investigator should sign a copy of the Standard Operating Procedures (SOPs).Besides, the investigator and his staff have to be aware and comply with SOP.ICH-GCP expects the investigator to comply with the protocol and leaves the task of monitoring compliance to SOPs to monitors and auditors.

Challenges-Investigator and Sponsor’s SOPs
This provision is practically impossible, as the sponsor will have to obtain signatures of all investigators in a trial on its large number of SOPs. Imagine the task of making multiple copies of hundreds of Sops, delivering them to investigators, and obtaining their signatures! Besides, SOPs also get revised periodically and the whole cycles have to be repeated.

Investigators Responsibility for Data Analysis
Usually data analysis is the function of the sponsor. However, this provision makes it a responsibility of the investigator, increasing his burden. The CRFs are never sent to IEC unless the IEC asks for them for some specific purpose

Challenges-Investigators Responsibility for data Analysis
The IECs of major institute, which are involved in several international trials, are already struggling to cope with large number of bulky documents submitted for their approval. This provision will increase IECs’ trouble, as they have to create space for bulky CRFs and the clinical trial reports.

Monitors’ Qualifications
Indian GCP guidelines (3.2) suggest that the monitor should have adequate medical, pharmaceutical and/or scientific experience.

Challenges-Monitors’ qualifications
As most monitors are pharmacists or scientific graduates, they would not have adequate medical experience and hence will not qualify as monitors.

Schedule Y
Schedule Y refers to requirement and guidelines to be followed in order to attain permission of importing and/or manufacturing New Drugs to market or to undertake clinical trials in India.

Challenges in Conducting Good Clinical Practices
-Inadequate and inaccurate records
-Failure to conduct the study according to the protocol
-Problems with informed consent
-Timely and accurate reporting of adverse events
-Failure to follow the approved protocol
-Resistance to Government regulation of clinical trials
-Ethical considerations.

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An exclusive workshop on fundamentals of ICH-GCP and clinical research

25. December 2009 by harshit.

We are in the process of organising a workshop on ICH-GCP guidelines, clinical conduct of the trial and its mangement, ethical and regulatory issues, role of quality and pharmacovigilance in India.

Our expert panel includes industry veterans like Mr. P.K. Rastogi (Ex Deputy controller general of India), a well known Investigator Dr. Naresh Gupta and several other to present their views on recent trends in clinical research with a deep insight on future of clinical research in
India.

The workshop will be held in Delhi for two days. It will cover several topics on basic principles, practical aspects of conducting trials. All doctors (MBBS, BHMS, BAMS), Life sciences graduates (Msc., Bsc.) and those who want to pursue a carrier in clinical research are cordially invited.

All the attendees will be provided with certificate of attendance.

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Top 5 Mistakes of RFP

17. December 2009 by harshit.

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Sponsors know that clinical trials are one of the most expensive endeavors for their company. Many sponsors would like to manage their trials in-house, but lack the needed infrastructure. Yet, sponsors have reservations outsourcing clinical research due to problems experienced working with CROs. These difficulties include lack of pricing clarity, poor communication, and inconsistent commitment to projects. In our experience, sponsors can better manage these issues by improving the processes they use when selecting CROs.

Sponsors typically select CROs in a competitive bid process. Sponsors issue a request for proposal (RFP) to a number of CROs. The RFP describes the project the winning CRO will perform. In addition, it instructs CROs to provide information the sponsor requires to identify the vendor that best meets its needs.

CROs then bid on the project by preparing a proposal. The sponsor reviews all proposals and awards the contract to one of the bidders.

The winning CROs proposal, premised on the RFP, establishes the foundation of the project plan. An inadequate RFP leads to inadequate proposals, which leads to an inadequate project plan. This, in turn, leads to budget creep, insufficient resources to complete the project, and the potential collapse of the relationship between sponsor and CRO

We have written proposals for CROs bidding on clinical projects valued at more than $10 million. Through this experience, we have seen poor RFPs as well as excellent ones. This article distils our experience and presents the five biggest mistakes sponsors make when preparing RFPs. Readers will learn what these mistakes are and gain insight into how to avoid these pitfalls. These mistakes include:

• Lack of proper preparation
• Omitting vital information
• Not verifying CRO qualifications
• Over reliance on bid grids
• Failure to properly evaluate pricing.
• Lack of proper preparation

Many sponsors issue RFPs before they have a sufficient understanding of their outsourcing needs. In some cases, this is okay if the sponsor is using a CRO to help finalize certain details of its clinical plan. However, if too much of the clinical plan is undeveloped, the sponsor gives the CRO power to design a plan they want, not the one the sponsor needs. The plan the CRO wants is the one that will win the contract.

CROs have learnt that, on average, a low price wins contracts. Moreover, they know that many sponsors will choose a proposal with a low price even if the proposed project plan does not reflect their needs.

Sponsors allow this to happen when they do not take the time to educate themselves on what their needs are. Thus, CROs will design a bare-bones project plan with a low price. Only once the project starts does the sponsor learn the extent of the services it actually needs, and the project’s scope and budget inflate. So, before issuing the RFP, sponsors should have a solid clinical plan.

Perhaps the sponsor will leave some details for the CRO to finalize. But the more the sponsor can tell the CRO, the more it retains the power to ensure the project plan and budget developed by the CRO are realistic. To do this, the sponsor must put in effort before issuing the RFP. It must thoughtfully map out its clinical program. If the company lacks the expertise to do this in-house, it should acquire expert help.

Omitting vital information

There is information CROs must have to develop a budget and work plan. In the absence of this information, CROs must make budget assumptions. Different CROs will choose different assumptions, undermining your ability to compare the costs from one CRO to another. Moreover, when CROs get to choose their budget assumptions, they tend to choose ones that make their costs look good.

It is true that in many cases sponsors may not know the details the CRO needs. Indeed, you may not know certain details, such as the number of queries per subject, until the study begins. In these cases, the sponsor should provide the budget assumptions in its RFP. If this is not possible—say, because you are asking the CRO to suggest the monitoring frequency—the RFP should clearly ask the CRO to state its assumptions, justify those assumptions, and provide a unit cost for the activity.
To help the CRO write a proposal, the RFP should provide:

The number and location of clinical sites
The number of subjects
Dates when enrollment starts and ends
Duration of follow-up
Proposed case report forms (CRFs) or a list of required CRFs
A schedule of assessments
An assumption of the number of queries per subject
An assumption of the number of serious adverse events per subject
Monitoring frequency
This list is far from complete. Given the range of services a sponsor might require, providing a complete list of the information needed by the CRO is beyond this article’s scope. There are, however, a number of resources available to sponsors, such as RFP manuals and templates. If you are unsure what information the CRO needs, ask them prior to submitting your RFP.

Not verifying CRO qualifications

A clinical trial is one of the most costly activities sponsors perform. Moreover, the future success of the sponsor is dependant on the trial’s results. Is it not worth some effort to ensure the CRO you hire is up to the task?

Sponsors should perform proper due diligence of the CRO they hire. This includes reference checks, review of financial information, study of staff turnover, and a site visit.

Reference check. The RFP should instruct the CRO to provide at least three references from customers who have had projects similar to yours run by the CRO. This is critical to ensuring the CRO is capable of delivering the work you are contracting out at the level of quality you need.

Financial check. The CRO industry is becoming more competitive. As a result, the number of CROs in the
United States is decreasing through attrition and consolidation. Should your CRO experience financial distress, this can jeopardize your project. Sponsors can assess this risk by asking the CRO to provide at least three years of financial statements. Someone with financial training at the sponsor should review this data to assess the CROs financial strength.

Staff turnover. High staff turnover at the CRO can be disruptive to your study. The RFP should instruct the CRO to provide turnover data. The sponsor can then compare the turnover data among bidding CROs. Note that you can define turnover in several ways. Thus, the RFP should define how to make this calculation. We recommend the method presented in Figure 1.

Site visit. A site visit allows you to verify with your own eyes the CRO’s abilities. In addition, when you hire a CRO their project team becomes a part of yours. Therefore, the compatibility of the two project teams is important. The site visit allows you to assess this compatibility.

Over reliance on bid grids

Unless instructed otherwise, each CRO will present its budget in its own format. To control for this, some sponsors present a bid grid in their RFP that instructs CROs how they want the budget presented.

In theory, this makes sense, as you can easily see where differences between CROs lie. In practice, though, there are shortcomings of relying too heavily on a bid grid. This stems from the fact that there are many ways a CRO can organize its workforce to perform a clinical trial. Each CRO organizes its budget to reflect its unique workflow. When you present it with a bid grid, it must now translate its budget into your grid. This requires discretion.
Consider the following: Where should a CRO allocate the cost for overseeing copying and shipment of paper CRFs from global sites to your data center? One CRO may file it under data management because they assign a data manager to oversee this task. In another, the monitor performs this function, so they allocate it to monitoring.

Once the CRO has allocated its expenses across your bid grid, it will review each category to see if any item seems too big or too small. It will then readjust how it allocated costs until the bid grid “looks about right.”

If the sponsor does provide a bid grid in its RFP, keep the details to a minimum. The bid grids provided from sponsors containing over 100 budget line items that contain minutia such as “Prepare Investigator Notebooks.” Imagine the effort required to compare the bids from three to five CROs across 100+ line items. Given the latitude CROs have in translating their budget to your bid grid, are differences across line items such as “Prepare Investigator Notebooks” very meaningful?

Dividing your bid grid into major categories, such as project management, data management, and so on is sufficient. Moreover, we recommend that sponsors not read too much into differences observed across categories in their grids. If the total budget of the most and least expensive CRO is within 25% of each other, then differences observed across the bid grid are probably not important.

Failure to properly evaluate pricing

Because of rising costs, sponsors obsessively search for the cheapest solution to their needs. To achieve this, they mercilessly drive down CRO rates and cut corners on their clinical plan. Unfortunately, many companies incur long-term costs in their search for short-term savings.

We have observed sponsors approach CROs they have short-listed and ask them to find ways to cut their price. CROs often respond by scaling back the services offered in their initial proposal, for example, by reducing monitoring frequency. Justifications for this will often include wording like, “Now that we understand your project better, we feel some of our earlier assumptions were too conservative.”

However, if the sponsor needs extra monitoring visits later, the CRO will bill this as an extra service. We have often observed that services removed from the proposal to lower costs end up being required. Many CROs bill for these “extra services” at a higher rate than activities scheduled in the proposal. Thus, not only do sponsors not get the savings they were expecting, they end up paying more than the CRO’s original plan. To reduce overall costs, companies need to stop looking for the cheapest solution and start looking for the best value.

Sponsors should do two things in their search for value. First, as stated, they must put effort into identifying their needs before issuing an RFP. Continuing with the earlier example, the sponsor should know the appropriate monitoring frequency for its study. Then, rather than allowing CROs to cut visits to reduce costs, sponsors should look for CROs that can deliver those visits for the best cost. If a CRO suggests a lower monitoring frequency, the sponsor should press them to justify their recommendation.

Secondly, once the sponsor has received proposals, it should select CROs based on value obtained per dollar, rather than the raw dollar amount of the proposal. To achieve this, sponsors can design a point system to grade proposals received—say, for instance, a score out of 100 total points. Dividing this score by the price quoted by the CRO yields a “value ratio.” This is the number of points the CRO scores per dollar. The higher the value ratio, the more value you are getting for your dollar

Improving CRO selection

Sponsors cannot abdicate the design of their clinical program to a CRO while grinding the CRO’s rates down and then expect they will get the study they need with a realistic budget. By improving processes to select CROs, sponsors can reduce overall costs and improve the quality of their program.

However, to achieve this, sponsors must educate themselves on their needs for the project. They must then translate these needs into an RFP that will lead CROs to develop a realistic project plan and budget. To reduce long-term project costs, sponsors must then evaluate each proposal and select the CRO that will provide the best value.

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