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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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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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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14. December 2009 by rahul.

Clinical trials involve subjects as well as patients. Recruitment and retention of patients are central to the exercise. Great care has to be exercised at every stage of patient induction. Availability of large patient population for enrolment in a proposed Clinical Trial is a Myth. Most of these patients vanish as the trial begins. Internationally, recruitment and retention of clinical trial patients are a big challenge. More than 80% of global trials fail to enroll on time, with 52% delayed by 1‐6 month .Failure to recruit patients on time leads to loss of over 85‐95% of days in a clinical trial. India has become an attractive country due to its potential for rapid recruitment of patients. Many optimistic estimates suggest that patient enrolment rates in India could be 3‐4 times faster than Western countries. However, the number of patients who complete the trial decides the success of a global trial.
More and more drugs on trial have been designed to attack very specific biological targets. This necessitates the need to identify, recruit and retain patients that fit an increasingly narrower medical profile. Therefore, pharmaceutical companies and clinical research organizations (CRO) are seeking new ways to optimize recruiting operations and gain a competitive edge. Operational delays in clinical trials reduce patent exclusivity time and shorten the most commercially productive phase of a product’s life cycle. This results in financial loss and missed market opportunities for potential blockbusters. The primary source of such delays is the recruitment and retention of patients that fit the trials ‘requirements.

Slow patient enrollment…reasons
1) Too rigid inclusion/exclusion criteria.
2) Poor motivation for Clinical Trial site personnel
3) Clinical Trial monitors not proactive
4) Competition for enrollment (financial Incentive greater from other sponsor)
5) Unrealistic enrollment expectations
6) Inaction against site specific reports by Clinical Trial Monitors

Recruitment tactics…..
1) Increase the accessible pt. population (increase time frame and CT sites)
2) Relax inclusion/exclusion criteria (progressively from phase 2 to phase 4, not to disturb pre‐set randomization)
3) Wider publicity (advertisement, internet). The Internet is an important tool to recruit both patients and physicians, but remains under‐utilized.
4) Clinical Trial sites and/or Clinical Investigators pressurized to increase patient enrollment, also inducing own patients to enroll.
5) Payments to other Investigators for enrolling their patients (Referrals)
6) Financial inducement to exceed targets
7) Penalties for sites not meeting targets.

Retention of enrolled patients/subjects…
1) Make patient partner in treatment
2) Explain to him/her the commitment to CT
3) Provide good quality professional care(minimize waiting period, listen patiently to complaints about treatment or ADRs, explain all queries regarding CTs)
4) Explain dosage schedule in detail and consequences of non‐adherence to schedule
5) Explain likely ADRs, and action if occurs
6) Financial package for enrollment in Clinical Trials
7) Incentive for completing Clinical Trial

In Non therapeutic trials, adequacy of Financial Package determines the size of your “Volunteer Bank”. In therapeutic trials, undisclosed personal financial incentives to Clinical Investigators are often used to increase patient recruitment rate or to exceed the target. For increasing recruitment, patient participation has to be increased. Protection of rights, well being and Confidentiality of patients has to be increased. All concerns of the patients for lack of efficacy or ADRs should be carefully attended to and assessed. It has to be remembered that “a satisfied patient is the best ambassador for patient enrolment in future C.T.’s by persuading the fence sitters “

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8. December 2009 by rahul.

Phthalates are chemicals that soften plastic. That new toy and new shower curtain smell is phthalates off gassing. They’re also found in medical supplies such as IV tubes and drip bags, plastic food wrapping and containers, and most ubiquitously in fragrances of every description, from scented candles and (so-called) air fresheners, to fabric softeners and perfumes. Phthalates block androgens, or male hormones, and can interfere with normal genital development in boys. Guys, if you want to make a baby, leave the cologne in the medicine cabinet, blow out the scented candles, Stop nuking your food in plastic and toss the hair gel. Phthalates literally block androgen receptors, so that male hormones can’t plug in and give their male hormone messages to cells. At this moment in human history, those of us who live in industrialized countries can’t get away from phthalates — they’re literally everywhere. But we can minimize our exposure by reading labels and opting for cleaner, greener products.

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8. December 2009 by rahul.

Confidentiality has become a growing concern. In the healthcare industry HIPAA regulations try to ensure an individual’s privacy by limiting access to medical records.HIPAA was enacted by Congress and signed into law by President William Clinton on August 21, 1996. The goal of HIPAA is to ensure that healthcare providers secure electronic records about patients in the same manner that hard copy records are secured. By securing the records, the healthcare industry can improve their level of services since improved security will lead to greater adoption of electronic transactions. One of the reasons that HIPAA was enacted was because the U.S. Federal Government wants all Medicare transactions to occur electronically by October 16, 2003. Before Congress could mandate patient records surrounding Medicare occur electronically, the security and privacy of patient records needed to be guaranteed.

Congress enacted HIPAA in response to the growing use of the Internet and electronic transactions. HIPAA is a privacy law to protect consumers from having their personal health information exploited by insurance companies, employers, and anyone else who may try to exploit, disclose, or publish their personal health information. In the Federal Register, HIPAA is more informally known as the Privacy Rule. Except in certain circumstances, individuals have the right to inspect, review and receive a copy of their medical and billing records that are held by health plans and healthcare providers. There are, however, some circumstances in which a patient would not be permitted to access his medical record. If a health care professional feels that the information requested could cause potential harm to either the patient or another individual, access could be denied. Other restricted health care information may include: psychotherapy notes, information gathered for legal proceedings, and laboratory results kept confidential by some research institutes.

Personal Health Information can be used for the following purposes, unrelated to health care:

1. As required by Law. Covered entities may use and disclose protected health information without individual authorization as required by law (including by statute, regulation, or court orders.

2. For Public Health Activities. Covered entities may disclose protected health information to: public health authorities authorized by law to collect or receive such information for preventing or controlling disease, injury, or disability and to public health or other government authorities authorized to receive reports of child abuse and neglect; entities subject to FDA regulation regarding FDA regulated products or activities for purposes such as adverse event reporting, tracking of products, product recalls, and post-marketing surveillance.

3. Victims of Abuse, Neglect or Domestic Violence. In certain circumstances, covered entities may disclose protected health information to appropriate government authorities regarding victims of abuse, neglect, or domestic violence.

4. Health Oversight Activities. Covered entities may disclose protected health information to health oversight agencies (as defined in the Rule) for purposes of legally authorized health oversight activities, such as audits and investigations necessary for oversight of the health care system and government benefit programs.

5. Judicial and Administrative Proceedings. Covered entities may disclose protected health information in a judicial or administrative proceeding if the request for the information is through an order from a court or administrative tribunal.

6. Decedents. Covered entities may disclose protected health information to funeral directors as needed, and to coroners or medical examiners to identify a deceased person, determine the cause of death, and perform other functions authorized by law.

7. Cadaveric Organ, Eye, or Tissue Donation. Covered entities may use or disclose protected health information to facilitate the donation and transplantation of cadaveric organs, eyes, and tissue.

8. Serious Threat to Health or Safety. Covered entities may disclose protected health information that they believe is necessary to prevent or lessen a serious and imminent threat to a person or the public, when such disclosure is made to someone they believe can prevent or lessen the threat (including the target of the threat). Covered entities may also disclose to law enforcement if the information is needed to identify or apprehend an escapee or violent criminal.

9. Workers’ Compensation. Covered entities may disclose protected health information as authorized by, and to comply with, workers’ compensation laws and other similar programs providing benefits for work-related injuries or illnesses.

HIPAA is far more complex than the Year 2000 date problem that information technology administrators faced in 1999, and that is why there are few guidelines available and few organizations providing compliancy services.

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4. December 2009 by rahul.

A medical device is a product which is intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals. Examples: include tongue depressors, medical thermometers, blood sugar meters, and X-ray machines.

Classification of Medical Devices
The regulatory authorities in recognize different classes of medical devices, based on their design complexity, their use characteristics, and their potential for harm if misused. Approximately 1,700 types of medical devices are regulated by FDA.Each of these generic types of devices is assigned to one of three regulatory classes based on the level of control necessary to assure the safety and effectiveness of the device.
The three classes and the requirements which apply to them are:
 Class I - General Controls
 Class II - Special Controls
 Class III - Premarket Approval

Class I - General Controls: Class I devices are subject to the least regulatory control as present minimal potential for harm to the user and are often simpler in design than Class II or Class III devices. Examples: elastic bandages, examination gloves, and hand-held surgical instruments.

Class II - Special Controls: Class II devices are those for which general controls alone are insufficient to assure safety and effectiveness.. Examples: powered wheelchairs, infusion pumps, and surgical drapes

Class III - Premarket Approval: Class III devices are usually those that support or sustain human life, are of substantial importance in preventing impairment of human health, or which present a potential, unreasonable risk of illness or injury. Premarket approval is the required process of scientific review to ensure the safety and effectiveness of Class III devices. Examples: replacement heart valves, silicone gel-filled breast implants, and implanted cerebella stimulators.

The basic regulatory requirements that manufacturers of medical devices must comply with :

1. Establishment registration 21 CFR Part 807: Manufacturers (both domestic and foreign) and initial distributors (importers) of medical devices must register their establishments with the FDA.

2. 2.Premarket Notification 510 (k)- 21 CFR Part 807 :A 510(k) is a premarket submission made to FDA to demonstrate that the device to be marketed is at least as safe and effective, that is, substantially equivalent, to a legally marketed device. Most Class I devices are exempt from the premarket notification and/or good manufacturing practices regulation.

3. Premarket Approval (PMA) - 21 CFR Part 814: Premarket approval (PMA) is the FDA process of scientific and regulatory review to evaluate the safety and effectiveness of Class III medical devices.

4. Investigational Device Exemption (IDE) - 21CFR Part 812: An investigational device exemption (IDE) allows the investigational device to be used in a clinical study in order to collect safety and effectiveness data required to support a Premarket Approval (PMA) application or a Premarket Notification 510(k) submission to FDA.

5. Good Manufacturing Practices (GMP) - 21 CFR Part 820: GMP includes requirements related to the methods used in: designing, purchasing, manufacturing, packaging, labeling, storing, installing and servicing of medical devices.

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2. December 2009 by rahul.

The 1572 is a federal form and is the statement of the investigator that he will abide by the federal guidelines set forth in the Code of Federal Regulations for the use of drugs in an investigational setting.
An investigator that is involved in drug or biologic research under Investigative New Drug (IND) regulations is obligated to sign a FDA form 1572. The PI signs a contract with the FDA which documents his or her agreement to follow the protocol and study obligations in conducting the trial. The investigator makes this contractual commitment when the FDA form 1572 (drug/biologic studies) or Investigator’s Agreement (device studies) is signed; the PI serves as the communication link between the sponsor and the FDA.
A new FDA 1572 Form must be submitted to the Program Management Board (PMB) whenever a change in any of the required information, such as the name or address of the PI or a change in the site IRB, occurs within the current year.
Regulation/Reference: 21 CFR 312
Purpose:
1. Document that the Investigator of Record (IoR) (i.e., Principal Investigator or PI)
agrees to conduct the trial according to the obligations stated in the form.
2. Update as study personnel and/or other data on the form changes.
3. The original version and any updated form must be retained as per regulatory
requirements.
4. The Investigator in box 1 of Form FDA 1572 is the individual who must sign and
date the signature box
5. Only laboratories specified in the protocol need to be listed in Section 4 to address
the following:
• Research /academic labs do not need to be listed on Form FDA 1572
• Research /academic labs should be listed in the protocol
• Central lab should be listed in the protocol for multi-center study protocol
• List individual clinical labs as in the protocol, unless it is a large multi-center
study and it would be impractical to list labs for every site.
1572 itself declares that, “No investigator may participate in an investigation until he/she provides the sponsor with a completed, signed Statement of Investigator, Form FDA 1572.” And FDA regulations at 21 CFR 312.53(c)(1) add that, “Before permitting an investigator to begin participation in an investigation, the sponsor shall obtain the following: (1) A signed investigator statement (Form FDA-1572)….” Therefore, the Form 1572 is a document that an investigator must submit to the study sponsor.
Through the 1572 Form and the attachments typically sent with it, an investigator provides a sponsor with, among other things, information on his or her education, training, and experience (CV or other statement of qualifications) that qualifies him or her to undertake the clinical investigation, information on the relevant facility, IRB, and sub investigators, protocol information, and the investigator’s commitment to conduct the study in accordance with the protocol and FDA regulations.

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