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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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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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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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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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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