My Clinicom Diary

Indian trial compensation guidelines open to comment

2011-12-01T21:14:00.000-08:00

India is seeking comments on draft guidelines that detail sponsors’ clinical trial injury compensation responsibilities.

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Indian trial compensation guidelines open to comment

Registration of BA/BE studies with CTRI to become mandatory soon

2011-11-03T22:01:00.000-07:00

After more than two years since the registration of clinical trials was made mandatory in the country, the Union health ministry will soon make the registration of bioavailability and bioequivalance (BA/BE) studies mandatory with the Clinical Trial Registry of India (CTRI).

According to sources, the Union health ministry has already taken the decision in-principle to make the registration of BA/BE studies mandatory, on the same lines of the other clinical trials in the country. The drugs controller general of India (DCGI) Dr Surinder Singh has already directed the senior officials in the CTRI to make the necessary changes in its web network to incorporate the BA/BE features, sources said.

According to sources, just like the clinical trials, the DCGI wanted to streamline the BA/BE studies in the country. So far, registration of BA/BE studies with the CTRI was optional. Once the DCGI makes it mandatory, all the BA/BE studies have to be registered with the CRTI without which the DCGI will not give permission to conduct BA/BE studies which are conducted on healthy volunteers.

Hundreds of BA/BE studies are going on at any given time in the country at different clinical research centres. BA/BE studies which take about three months time, are conducted for finding the bioavailability and bioequivalance of a drug, especially the generic drugs and the combination drugs which are already in the market. For getting the license for a new combination drug or generic drug, it is mandatory to submit the BA/BE study results to the DCGI office.

The CTRI was set up by the National Institute of Medical Statistics (NIMS) which is an arm of Indian Council of Medical Research (ICMR) and is funded by the Department of Science and Technology (DST) through ICMR. It also receives financial and technical support through the WHO, WHO-SEARO, and the WHO India Country office.

The main objective of the CTRI is to ensure that every clinical trial conducted in the region is prospectively registered with full disclosure of the 20-item WHO ICTRP dataset, as well all items of the CTRI dataset, in order to improve transparency and accountability; improve the internal validity (details of the methods of the trial that produce reliable results, primarily the method of random sequence generation, concealment of allocation, blinding of participants and investigators, and inclusion of all participants results) of trials right from the design,through conduct and reporting; conform to accepted ethical standards; and lead to reporting of all relevant results of all clinical trials in India and the region.

ROLE OF ETHICS COMMITTEES

2011-11-03T08:21:00.000-07:00

The most costly part of new drug discovery is the three phase clinical research lasting for three to four years involving thousands of human volunteers and investigators in multi locations. Any of these potential drug candidates can be abandoned during the trial period if their adverse drug events are beyond the acceptable limits.

It is certainly a high risk activity involving millions of dollars and pharmaceutical companies usually make sure that trial reports reaching the regulatory authorities are favourable. No new drug can be approved for marketing without submission of trial reports and their scrutiny by the regulatory authorities. Because of these reasons, the whole operation of clinical research is highly secretive.

Apart from top MNCs like Pfizer, GSK, Novartis and Novo Nordisk, there are a large number of contract research organizations engaged in clinical trials in India for the last ten years.

As thousands of human subjects are recruited for each drug trial, the regulatory authorities have a responsibility to monitor the trial locations. And it is for this purpose, the Schedule Y of the Drugs & Cosmetics Act stipulates the existence of an ethics committee at each trial site.

But for many years, ethics committees have not been existing or non functional in India. It is this ineffectiveness of ethics committees that embolden the CROs and MNCs to carry out trials illegally endangering the lives of illiterate and ignorant volunteers.

The decision of the Drug Technical Advisory Board to make registration of ethics committees mandatory at its meeting early last month is in consideration of this state of affairs. There has been several complaints about the non functioning of ethics committees at most of the trial sites. It is this situation that has led to a sharp rise in the number of cases of trial related deaths and injuries in the country during the last five years.

Currently, ethics committees are constituted by the pharma companies or CROs intending to conduct trials but they are not required to be registered. For starting any clinical trial, the approval of the ethics committee is necessary as without which the DCGI do not permit the study in the country. But the ethics committees are not found to be responsible once the approval is given. No periodic meetings with investigators are called and no critical assessment of data is made. And there is no monitoring of the functioning of the ethics committee by the office of DCGI.

The need to streamline activities of ethics committees is extremely urgent considering the growing number of clinical trials taking place in the country. Making registration of ethics committees is an extremely critical step and needs to be strictly enforced without any delay.

Compensation package for clinical trial victims in the offing

2011-10-23T21:56:00.000-07:00

NEW DELHI: India will soon quantify the amount of compensation to be paid by pharmaceutical companies, if a volunteer dies or gets injured during a clinical trial.

On October 10, the Drug Technical Advisory Board (DTAB) gave its nod to the Central Drugs Standard Control Organization (CDSCO) to prepare a "compensation chart" or extensive guidelines that will specify the amount to be paid.

Ethical committees of the company will have to decide the quantum of compensation on the basis of these guidelines.

The compensation has to be paid by the trial's sponsor or its representative within 90 days of the death or injury to the victim or the next of h/his kin. In the first 30 days, the firm will have to prove to the ethics panel that the death or injury wasn't due to the drug, else it has to pay.

In India, pharma companies pay compensation "according to their will" that varies between Rs 1 lakh and Rs 10 lakhs since "no set parameters have been laid down".

The CDSCO will prepare the compensation guidelines after consulting the Motor Vehicles Act, Railways and the Workers Compensation Act.

Union health ministry officials say it will take another three months to notify the guidelines. "When a 70-year-old terminally ill patient dies during a clinical trial, the compensation should be less than that given to a 22-year-old in the first stage of the same ailment. The youngster could be the family's sole bread-winner and would have lived longer had it not for the adverse drug reaction. The guidelines will quantify who should get how much compensation," a ministry official told TOI.

"Both these patients could get the same amount. However, the pharma company might have decided on an abysmally low package. Once the guidelines are in place, the division of compensation will be fair," he added.

Families of the 22 clinical trial victims last year were paid around Rs 50 lakh by 10 pharma companies.

Compensation ranged from Rs 1.08 lakh to Rs 10 lakh. Most of the families received Rs 1.5 lakh and Rs 2.5 lakh as a one-time package.

Initially, the companies had not paid compensation for majority of these deaths. Then, DCGI Dr Surinder Singh issued an ultimatum to the errant firms: pay up or all other trials would be suspended.

The companies who paid the compensation included well-known names like Wyeth, Quintiles, Lilly, Amgen, Bayer, Bristol Mayer, Sanofi, PPD and Pfizer. Pharma companies have all along been blamed for not paying compensation to hapless clinical trial victims.

The Indian Council of Medical Research recently framed draft guidelines for compensation to participants for research-related injury. Mothers, who because of clinical trials, lose or cause harm to their unborn child may be able to demand compensation from researchers conducting the trials.

Compensation has to be paid, irrespective of whether injury was foreseeable/predictable, and that the research participant had freely consented in writing about participating in it.

Compensation will have to be provided to the research participants when temporary or permanent injury occurs due to participation in the clinical study.

Compensation also has to be paid when the injury is caused by a procedure that has been undertaken to manage an adverse reaction occurring during the research.

Defining "compensation", the draft says it could be in form of payment for immediate medical/surgical management of research-related injuries, compensation for research-related injuries leading to temporary or permanent disabilities or compensation to legal heir/lawful guardian in case of death.

"The payment will be the responsibility of the investigator/institution," it says.

Besides, the Informed Consent Document (ICD) will have to state that the research participant has the right to claim compensation in case of research-related injuries and whom to contact for it.

Article source: Times of India

CTRI Confirms Leading Indian CRO Supports Majority of Hemophilia Trials in India

2011-10-20T22:03:00.000-07:00

Max Neeman International is the only CRO in India to manage hemophilia trials according to the Clinical Trials Registry-India (CTRI). Of the total hemophilia trials currently being conducted in India, Max Neeman can boast supporting 80% of these with the remaining conducted by pharma companies.

Max Neeman International has established a team of experts specialized in carrying out hemophilia trials in response to sponsor demand. The team has the required expertise via involvement of academia with industry, hemophilia trial experience and extensive database of best Investigators for indication to develop innovative approaches to optimize complex study design. Often strict inclusion/exclusion criteria and data analysis for such studies create the greatest challenge for Biotech and Pharma that the company's expertise can address.

Max Neeman is a leading CRO in India that has a focus on hemophilia and bleeding disorder studies, in addition to other indications. Patient enrollment for complex global and multi-centric hemophilia trials is challenging because potential subjects are fewer in number and widely dispersed. With an Incidence of 1 in 10,000 people, India has more than 120,000 hemophilic and thus it has evolved into a preferred destination for conducting such trials because of low cost and faster patient recruitment.

Source: PRNewswire

BE guidelines regarding investigator

2011-10-14T08:52:00.000-07:00

BE guidelines recommend investigator should possess appropriate medical qualification, experience for conducting pharmacokinetic studies

Can chairperson of EC directly write to sponsor to clarify some of the queries of clinical trial raised in EC meeting?
Dr. Sreevatsa

Please see an extract from FDA's comment on IRB-sponsor relationship.

The interrelationship and interaction between the research sponsor (e.g., drug, biologic and device manufacturers), the clinical investigator and the Institutional Review Board (IRB) may be very complex. The regulations do not prohibit direct sponsor-IRB contacts, although, the sponsor-IRB interaction customarily occurs through the investigator who conducts the clinical study.

The clinical investigator generally provides the communication link between the IRB and the sponsor. Such linkage is agreed to by the sponsors and investigators when they sign forms FDA-1571 and FDA-1572, respectively, for drug and biologic studies or an investigator agreement for device studies. There are occasions when direct communication between the IRB and the sponsor may facilitate resolution of concerns about study procedures or specific wording in an informed consent document. The clinical investigator should be kept apprised of the discussion.

In the scenario you have described, it is the investigator who is asking EC to approach sponsor. This is not acceptable. The EC has to put questions to investigator and he has to get responses from sponsor.

Is it mandatory to be a principal investigator (PI), one needs to be a clinical pharmacologist, or qualified (medical graduate without specialization) with enough experience can perform the duties of PI for BA/BE studies in particular and clinical trials in general?
Dr. K. Sudhakar Reddy
None of the guidelines prescribe a degree for the PI. The guidelines stress on training and experience for carrying out all responsibilities of PI as required by the protocol, GCP, and regulations.

Indian BE guidelines recommend:
The investigator should possess appropriate medical qualification and relevant experience for conducting pharmacokinetic studies.

Indian GCP recommends:The investigator should be qualified by education, training and experience to assume responsibility for the proper conduct of the study and should have qualifications prescribed by the Medical Council of India (MCI).

Schedule Y and Indian GCP recommend the need for a clinical pharmacologist for phase I, see the definition:
Human/Clinical pharmacology trials (phase I).
Phase I trials are usually carried out by investigators trained in clinical pharmacology and having the necessary facilities to closely observe and monitor the subjects.
However, for phase II-III trials, the PI has to be qualified in the discipline and experienced. E.g. for a study in stable angina, the PI has to be an MD who is licensed to practice as a physician and who is treating/managing such patients. However, if the trial includes angioplasty, she/he has to be a cardiologist who is experienced in the procedure.

What is the current situation of regulations for medical devices? Rajesh Krishnan
The regulatory approach to devices is under development. In general DCGI office treats device along the drug lines. In August 2010, CDSCO has released to draft guidance for common submission format for registration of medical devices in India requirements for conducting clinical trial(s) of medical devices in India.

Is there any guideline in ICMR, DCGI regarding herbal related trial?
Kunal
Ayush has recently released guidelines on GCP for clinical research on Ayurveda, Siddha and Unani medicines and other traditional medicine.

Indian GCP covers a section on Herbal. The approach to regulatory depends on the category of product described in the guidelines.(see below).

7.5.1. Categories of Herbal Products
The herbal products can belong to any of the three categories given below:

a) A lot is known about the use of a plant or its extract in the ancient Ayurveda, Siddha or Unani literature or the plant may actually be regularly used by physicians of the traditional systems of medicine for a number of years. The substance is being clinically evaluated for same indication for which it is being used or as has been described in the texts.

b) When an extract of a plant or a compound isolated from the plant has to be clinically evaluated for a therapeutic effect not originally described in the texts of traditional systems or, the method of preparation is different, it has to be treated as a new substance or new chemical entity (NCE) and the same type of acute, sub acute and chronic toxicity data will have to be generated as required by the regulatory authority before it is cleared for clinical evaluation.

c) An extract or a compound isolated from a plant which has never been in use before and has not ever been mentioned in ancient literature, should be treated as a new drug, and therefore, should undergo all regulatory requirements before being evaluated clinically.

In India, there is no separate guidance on pregnancy reporting

2011-08-19T22:26:00.000-07:00

How will we conclude that the subject is illiterate?
Dr Prakash Atlam
The guidelines don’t use the term illiterate. Their focus is subject’s ability to read and/or write.

Schedule Y treats anyone who is unable to read or write in the same way. See the excerpt below.

If the subject or his/her legally acceptable representative is unable to read/write - an impartial witness should be present during the entire informed consent process who must append his/her signatures to the consent form.

While designing a protocol we found that there are high likely chances of worsening of some of the symptoms. Do we have to wait for these to happen and report it as SAE or in case we define them in the protocol upfront then can we prevent from expediting reporting it as SAE?
Om
Please see suggested guidance from ICH. Exemption from reporting such events would require prior agreement with regulatory authorities.

ICH E3 12.2.2 Display of Adverse Events: All adverse events occurring after initiation of study treatments (including events likely to be related to the underlying disease or likely to represent concomitant illness, unless there is a prior agreement with the regulatory authority to consider specified events as disease related) should be displayed in summary tables (section 14.3.1). The tables should include changes in vital signs and any laboratory changes that were considered serious adverse events or other significant adverse events. In most cases, it will also be useful to identify in such tables "treatment emergent signs and symptoms" (TESS; those not seen at baseline and those that worsened even if present at baseline).

ICH E9 In situations when there is a substantial background noise of signs and symptoms. (e.g. in psychiatric trials) one should consider ways of accounting for this in the estimation of risk for different adverse events. One such method is to make use of the “treatment emergent' (see Glossary) concept in which adverse events are recorded only >if they emerge or worsen relative to pretreatment baseline.

Other methods to reduce the effect of the background noise may also be appropriate such as ignoring adverse events of mild severity or requiring that an event should have been observed at repeated visits to qualify for inclusion in the numerator. Such methods should be explained and justified in the protocol.

In a two period cross-over BA/BE study, if any AE occurs on the day of dosing of period-2 but before dosing of period-2 e.g. fever. Then obviously the subject will not be dosed for period-2. In this case, in which AE form we should record the AE i.e. AE form for period-1 or period-2. Because all the information like relationship to the study medication, last dosing date & time, treatment code and time elapsed since last dosing etc will be considered with respect to dosing time and date of period-1 only. Please suggest in which AE form we should record the pre-dose AEs of period-2 i.e. AE form for period-1 or Period-2.
Dr Muneesh Garg
Going by the logic and practice of clinical trials, as the subject was screened and was waiting to be enrolled for period 2, the AE would be recorded in period-2 form. On the other hand, in clinical trials adverse events are followed up-to 30 days after the last visit/completion of protocol. By this logic, one can consider the AE as occurring in post-period 1 drug follow-up.

As long as the details are captured in the form, it would not matter in which form you capture period 1 or 2. In clinical trials, we use only 1 AE page. The details filled on the page are adequate to relate the drug to the causality assessment.

Let me know whether pregnancy detected after completion of one period of a BE study is an SAE?
Nanda Kumari
Pregnancy is special medically significant condition SAE requiring reporting.

Internationally, pregnancy is reported separately. In India, there is no separate guidance on pregnancy reporting. Hence, it will be reported as an SAE.

Is there any difference between Independent EC and Institutional EC?
Dr Sreevatsa
The only difference is their location. Institutional ECs function in Institutions. (GCP Definition: Institution - any public or private medical facility where a clinical study is conducted). The ECs which are not attached to any institution are considered private ECs abroad and independent ECs in India. However, the major difference is in their scope of authority. If there is a trial in an institution, the investigator has to seek approval of the institutional EC

Source: Pharmabiz

ICH GCP requires EC members to be independent of investigator and sponsor to avoid conflicts of interest

2011-06-09T22:13:00.000-07:00

Can an Ethics Committee member e.g. layman/chairman or anyone in the committee participate in the trial as a subject?

Vidya
If an Ethics Committee member becomes a trial subject on a trial that he/she was involved in approving then there has been a major conflict of interest. The following situations need to be considered:
● IEC member reviews study without any prior knowledge of the study, votes, and then afterwards is approached by clinical research team to participate. Possibly this is OK but the member should no longer be part of the IEC that reviews that study. This will be difficult in practice, so therefore it is not advisable.
● IEC member already knows about the study and is voting in order to be able to participate. This is clearly not acceptable and made worse if there is additional financial incentive for the study (e.g. volunteer study).

ICH GCP requires Ethics Committee members to be independent of the investigator and the sponsor to avoid conflicts of interest.

Is it mandatory to have a qualified pharmacist for pharmacy activities like for dispensing?
Chetan Shingala
I assume your question pertains to site. As per ICH-GCP, the site can have a pharmacist or another individual for IP related responsibilities. See below.

4.6 Investigational product(s)
4.6.2Where allowed/ required, the investigator/ institution may/should assign some or all of the investigator's/institution’s duties for investigational product(s) accountability at the trial site(s) to an appropriate pharmacist or another appropriate individual who is under the supervision of the investigator/institution.

4.6.3
4.6.3The investigator/institution and/or a pharmacist or other appropriate individual, who is designated by the investigator/institution, should maintain records of the product's delivery to the trial site, the inventory at the site, the use by each subject, and the return to the sponsor or alternative disposition of unused product(s). These records should include dates, quantities, batch/serial numbers, expiration dates (if applicable), and the unique code numbers assigned to the investigational product(s) and trial subjects. Investigators should maintain records that document adequately that the subjects were provided the doses specified by the protocol and reconcile all investigational product(s) received from the sponsor.

In an investigator initiated trial the interventions are: one group assigned an approved drug (for same indication) in India and the control group with life style modification. The question is a) Is this a randomized controlled trial or an observational study or other designs? b) What phase of trial is this? c) Do we need DCGI approval?
J. Vijayakumar
● This is clinical trial as you are comparing two interventions. As the comparison is between a drug and a non-drug measure, it is difficult to randomize and blind the study. It will be desirable to have blinded observers and objective endpoints, if the trial results are to be considered valid.
● It’s a Phase IV as the drug is being used for approved indication.
● DCGI approval is not needed.

See ICMR 2006 guidelines excerpt below:There are Phase IV studies that are designed to evaluate the marketed drug in specifically designed studies, which have inclusion/exclusion criteria, objectives and end points. The drug is used for the labeled indication in these studies. Therefore Licensing Authority permission is not needed. However, EC permission is needed.

If one patient has reported the same adverse event throughout the study, are we supposed to count it as one adverse event or are we supposed to count it visit wise? For e.g. if the patient has reported nausea continuously from day 0 to day 14 and if there are 4 visits during day 0 to day 14, then are we supposed to count nausea as one single adverse event or it will be counted as different adverse events?
Shruti Kulkarni
It depends on whether the first event subsided or is continuing. If the first event has subsided, and if the subject complaints of the same event again, it will be considered a new event. If the event has not subsided, only one event will be reported as continuing.

Ethics Committee has their own SOP and their own format for approval. Is it necessary to have approval in Schedule Y format?
Dr. Hemant Zaveri
The EC can have its own format. But the approval format should cover all requirements of Schedule Y.

Source: Pharmabiz

A change in inclusion/exclusion criteria will require approval from DCGI

2011-05-12T08:39:00.000-07:00

Is it necessary to obtain DCGI/EC approval for clinical trial of nutraceutical and register the trial in CTRI? Is it essential to carry out toxicity studies? Binu Kuruvilla DCGI approval is not required unless the indication claim is as per definition of a new drug as per Drugs & Cosmetics Rules.

The definition of drug is as follows: All medicines for internal or external use of human beings and all substances intended to be used for or in the diagnosis, treatment, mitigation or prevention of any disease or disorder in human beings.

In addition, you should consider new drug definition as per Rule 122E.

A drug is considered a new drug if
1) it is a new chemical, biological or recombinant bio-technological or such devices or delivery systems
2) a drug already approved for certain claims is now being considered for modified or new claims, namely, indications, dosage, dosage form (including sustained release dosage form) and route of administration
3) fixed dose combination of two or more approved drugs, which are now proposed to be combined for the first time in a fixed ratio, or if the ratio of individual drugs already marketed combination is proposed to be changed, with certain claims, viz. indications, dosage, dosage form (including sustained release dosage form) and route of administration EC approval is essential. Registration of clinical trial in CTRI is voluntary. The requirement of toxicity depends on the available human safety data of nutraceutical and duration of the treatment with the nutraceutical in the clinical trial.

What is the current situation of investigator initiated trials in India - applicable regulations, investigators keenness, funds?

Shilpi Ray The regulations do not describe investigator initiated trials. However, in light of current MCI Code and CDSCO approach, these are treated like any other trial i.e. investigator IND. If the trial is industry sponsored, it is treated like a typical regulatory approval trial. However, if the trial is an investigator's personal research, requirements are less stringent e.g. a protocol and publication supporting the objectives may suffice. In my experience, very few investigators are keen on such trials. Usually they expect industry to fund and take care of all issues - regulatory/ethics approval etc.

What is a registry study? Dr Nitin Kulkarni Registry is one approach in Phase IV post-marketing stage. Registries are conducted in a real world setting with the objective of measuring a product’s effectiveness, and are useful in validating the safety and efficacy of interventions seen in controlled clinical trials into everyday practice. The patient registries allow large-scale/long-term data collection without high cost of traditional Phase IV studies. The patient registries also provide an opportunity to collect relevant information relating to interventions, such as: physician experience, patient-reported outcomes, and burden of illness.

Is BE study of new oncology molecule allowed in Indian patients, if the drug is not available in the Indian market? Is the new liposomal formulation of an old drug considered new medical entity? Is Phase I trial for new formulation of a European sponsor allowed?
Chirag Shah Yes, you can get approval for BE study from DCGI for a new drug. As per Drugs and Cosmetics Act 122 E a new formulation is considered a new drug. If the Phase I is for a new medicinal entity discovered outside India, Phase I will not be allowed.

If the protocol version is changed due to some minor changes in inclusion and exclusion criteria, do we need DCGI approval or notification is enough?
Rashmi A change in inclusion/exclusion criteria will require approval from DCGI office. Please see the CDSCO guidance on protocol amendment.
■ Those amendments which do not require notification to or permission of the licensing authority
● Administrative and logistic changes
● Minor protocol amendments and additional safety assessments in case the institutional ethics committee has already approved these changes
● Those amendments which require notification to the licensing authority but need not wait for permission
● Additional investigator sites
● Change in investigator with the consent to withdraw from the earlier investigator
● Amended investigators brochure, amended informed consent
■ Those amendments which require prior permission of the licensing authority
● Additional patients to be recruited
● Major changes in protocol with respect to study design, dose and treatment options
● Any change in inclusion or exclusion criteria.

Dr Arun Bhatt is currently, president, ClinInvent, Research Pvt Ltd, Mumbai. Readers can send their queries at: arunbhatt@clininvent.com

Source: Pharmabiz

EC chairperson can serve as legal expert during the meeting

2011-04-15T08:47:00.000-07:00

Please clarify re: patient reported outcome (PRO) instruments:
1) Post translations whose responsibility is it to validate the translated version of the questionnaire?
2) Could the translated version be submitted to the regulatory authority without validation?
3) Whose responsibility is it to submit the translated questionnaire post validation?
4) If any modification is done in the validated translated version then is there a requirement to validate the modified version and then submit the same to the regulatory authority?
5) What if a translated questionnaire is used without validation considering a situation where only English document has been submitted to the regulatory authorities and the translated version have only been submitted to the respective Ethics Committees?

Garima Singh

For 1) & 3) - FDA has released a guidance on PRO in Dec 2009. It is addressed to sponsors. Hence, they are responsible for validation of the PRO instrument - both English as well as translations.
For 2) - The FDA expects the sponsor to submit validated translations (see below appendix to the FDA guidance).
VIII. Language Translation and Cultural Adaptation

Process used to translate and culturally adapt the instrument for populations that will use them in the trial
Description of patient testing, language- or culture-specific concerns, and rationale for decisions made to create new versions.
Copies of translated or adapted versions
Evidence that content validity and other measurement properties are comparable between the original and new instruments

For 4) - If there is a modification, following documents are required.

Any change in the original instrument (e.g., wording of items, response options, recall period, use in a new population or indication)
Rationale for and process used to modify the instrument
Copy of original and new instruments
Evidence that content validity and other measurement properties are comparable between the original and modified instruments (including use in a new indication or population).

For 5) - It would be necessary to validate the translated instrument before using it in the patients. So even if it submitted/approved by EC, the validation is a must. Also, as per FDA guidance, the validated translation must be submitted to FDA.

Can EC chairperson act as legal expert during the meeting (dual role)? Please let me know if in this case, EC quorum met as per Schedule Y?

A. Mohammed Asif

The chairperson can serve as a legal expert. However, the person should be officially designated in the EC SOPs as legal expert for all meetings/quorum. The quorum requires the following EC members representing different roles
For review of each protocol the quorum of Ethics Committee should be at least 5 members with the following representations:

basic medical scientists (preferably one pharmacologist).
clinicians
legal expert
social scientist / representative of non-governmental voluntary agency / philosopher / ethicist / theologian or a similar person
lay person from the community.

It does not give EC titles e.g. chairperson. Hence, a chairperson serving as a lawyer can fulfill the requirements of quorum.

Protocol requires that when study drug X+Y is to be administered, drug Y is supposed to be administered first, followed by a normal saline flush, then drug X to be administered. In one patient, drug X was administered first then Y. Is it a protocol deviation or violation?

Praveen

There is no official definition of protocol violation / deviation. However, some guidance is given below:

EFGCP Audit Working
Party 2001
Protocol Violation: Serious non-compliance - may lead to exclusion of patients from eligibility analysis and/or their discontinuation from the study
Protocol Deviation: Less serious non-compliance - may not render a patient ineligible
Norman M. Goldfarb J of Clinical Research Best Practices Nov 2005

Protocol Deviation. A protocol deviation occurs when, without significant consequences, the activities on a study diverge from the IRB-approved protocol, e.g., missing a visit window because the subject is travelling. Not as serious as a protocol violation.
Protocol Violation. A divergence from the protocol that materially (a) reduces the quality or completeness of the data, (b) makes the ICF inaccurate, or (c) impacts a subject’s safety, rights or welfare. Examples of protocol violations may include:

Inadequate or delinquent informed consent
Inclusion/exclusion criteria not met
Unreported SAEs
Improper breaking of the blind
Use of prohibited medication
Incorrect or missing tests
Mishandled samples
Multiple visits missed or outside permissible windows
Materially inadequate record-keeping
Intentional deviation from protocol, GCP or regulations by study personnel
Subject repeated non-compliance with study requirements

Please find out why the protocol requires IP administration in a specific way. Is there any impact on efficacy / safety if the order of administration is reversed? Is there a pharmaceutical / pharmacological / pk interaction between 2 drugs? If so, it will be a protocol violation.

Source: Pharmabiz

Good Clinical Practices

2011-04-11T08:23:00.000-07:00

Clinical research is the key to the discovery of latest diagnostic methods and to develop modern drugs for treatment of diseases. Good Clinical Practices (GCP) is an ethical and scientific quality standard for designing, conducting and recording trials that involve the participation of human subjects. Compliance with this standard provides assurance to public that the rights, safety and well being of trial subjects are protected, consistent with the principles enshrined in the Declaration of Helsinki and ensures that clinical trial data are credible.

It has been widely recognized that India offers unique opportunities for conducting clinical trials in view of the large patient pool, well- trained and enthusiastic investigators and premiere medical institutes available in the country along with considerable low per patient trial cost, as compared to developed countries.

A need was, however, felt to develop our own Indian Guidelines to ensure uniform quality of clinical research throughout the country and to generate data for registration for new drugs before use in the Indian population. An Expert Committee set up by Central Drugs Standard Control Organisation (CDSCO) in consultation with clinical expert has formulated this GCP guideline for generation of clinical data on drugs.

The Drug Technical Advisory Board (DTAB), the highest technical body under D&C, Act, has endorsed adoption of this GCP guideline for streamlining the clinical studies in India.

Contents

Introduction
1. Definitions

2. Pre-requisites for the study

2.1. Investigational Pharmaceutical Product

2.2. Pre-Clinical supporting data

2.3. Protocol

2.3.1. Relevant components of Protocol

2.3.1.1. General Information

2.3.1.2. Objectives and Justification

2.3.1.3. Ethical Considerations

2.3.1.4. Study design

2.3.1.5. Inclusion, Exclusion & Withdrawal of Subjects

2.3.1.6. Handling of the Product(s)

2.3.1.7. Assessment of Efficacy

2.3.1.8. Assessment of Safety

2.3.1.9. Statistics

2.3.1.10. Data handling and management

2.3.1.11. Quality control and quality assurance

2.3.1.12. Finance and Insurance

2.3.1.13. Publication policy

2.3.1.14. Evaluation

2.3.2. Supplementaries and appendices:

2.4. Ethical & Safety Considerations

2.4.1. Ethical Principles

2.4.2. Ethics Committee

2.4.2.1. Basic Responsibilities

2.4.2.2. Composition

2.4.2.3. Terms of Reference

2.4.2.4. Review Procedures

2.4.2.5. Submission of Application

2.4.2.6. Decision Making Process

2.4.2.7. Interim Review

2.4.2.8. Record Keeping

2.4.2.9. Special Considerations

2.4.3. Informed Consent Process

2.4.3.1. Informed Consent of Subject

2.4.3.2. Essential information for prospective research subjects

2.4.3.3. Informed Consent in Non-Therapeutic Study

2.4.4. Essential Information on Confidentiality for Prospective Research Subjects

2.4.5. Compensation for Participation

2.4.6. Selection of Special Groups As Research Subject

2.4.6.1. Pregnant or nursing women

2.4.6.2. Children

2.4.6.3. Vulnerable groups

2.4.7. Compensation for Accidental Injury

2.4.7.1. Obligation of the sponsor to pay

3. Responsibilities

3.1. Sponsor

3.1.1. Investigator and Institution Selection

3.1.2. Contract

3.1.3. SOP

3.1.4. Allocation of duties and responsibilities

3.1.5. Study management, data handling and record keeping

3.1.6. Compensation for Participation

3.1.7. Confirmation of review by the Ethics Committee

3.1.8. Information on Investigational Products

3.1.9. Supply, storage and handling of Pharmaceutical Products

3.1.10 Safety Information

3.1.11 Adverse Drug Reaction Reporting

3.1.12 Study Reports

3.1.13 Monitoring

3.1.14 Audit

3.1.15 Multicentre Studies

3.1.16 Premature Termination or Suspension of a Study

3.1.17 Role of Foreign Sponsor

3.2. The Monitor

3.2.1. Qualifications

3.2.2. Responsibilities

3.3. Investigator

3.3.1. Qualifications

3.3.2. Medical Care of the Study Subjects

3.3.3. Monitoring and Auditing of records

3.3.4. Communication with Ethic Committee

3.3.5. Compliance with the Protocol

3.3.6. Investigational Product(s)

3.3.7. Selection and recruitment of Study Subjects

3.3.8. Records/Reports

4. Record Keeping and Data Handling

4.1. Documentation

4.2. Corrections

4.3. Electronic Data Processing

4.4. Validation of Electronic Data Processing Systems

4.5. Language

4.6. Responsibility of Investigator

4.7. Responsibilities of Sponsor and Monitor

5. Quality Assurance

6. Statistics

6.1. Role of Biostatistician

6.2. Study design

6.2.1. Randomisation and Blinding

6.3. Statistical Analysis

7. Special Concerns

7.1. Clinical Trials of Vaccines

7.1.1. Phases of Vaccine Trials

7.1.2. Guidelines

7.2. Clinical Trials of contraceptives

7.3. Clinical Trials with Surgical Procedures / Medical devices.

7.3.1. Definitions

7.3.2. Guidelines

7.4. Clinical Trials for Diagnostic agents - Use of radioactive materials and X-rays

7.4.1. Guidelines

7.5. Clinical Trials of Herbal Remedies and Medicinal Plants

7.5.1. Categories of Herbal Product

7.5.2. Guidelines

Appendices
Appendix I: Declaration of Helsinki
Appendix II: Schedule Y

Appendix III: Format for submission of Pre-clinical and clinical data for r-DNA based vaccines, diagnostics and other biologicals.

Appendix IV: Investigator's Brochure
Appendix V: Essential Documents

Good Clinical Practice Guidelines...continue reading here: http://cdsco.nic.in/html/gcp1.html

Registration of herbal trials in CTRI is not mandatory

2011-03-25T08:49:00.000-07:00

A trial patient visited the site complaining breathlessness and tachycardia. The investigator advised hospitalization but as subject could not afford the expenses, he refused for admission. Is this an SAE because investigator advised hospitalization?

G Praveen Kumar.

If the patient was not hospitalized, it does not fall into SAE criteria of hospitalization. However, it appears from your mail that the PI felt that the event was serious enough to admit the subject for treatment. This makes it an “important medical event." As per ICH E2A such event also are considered serious. See the ICH E2A excerpt below:

Medical and scientific judgement should be exercised in deciding whether expedited reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalisation but may jeopardise the patient or may require intervention to prevent one of the other outcomes listed in the definition above. These should also usually be considered serious.

There is also one more problem here. As per Indian GCP, and recent DCGI directive, the cost of medical treatment has to be covered by the sponsor. Hence, the PI should have treated the patient free of charge and recovered the cost from the sponsor.

How often should the ICF be updated considering there are CIOMS generated on an ongoing basis during the course of a trial?

Garima Singh

As per ICH E6, section 4.8.2, the written ICF and any other written information provided to subjects should be revised whenever important new information becomes available that may be relevant to the subjects consent. It also states that the IRB/IEC, the subject or the LAR should be informed in a timely manner if new information becomes available that maybe relevant to the subjects willingness to continue participation in the trial.

If the CIOMS contains information that is relevant to the subject’s consent then the ICF needs to be updated. Also 21 CFR 50.25 (b) states that significant new findings developed during the course of research which may relate to the subjects willingness to continue participation will be provided to the subject.

IB needs to be updated annually, but what if there are no safety updates in a particular year?

Garima Singh

As per ICH-GCP, the IB should be reviewed at least annually and revised as necessary in compliance with a sponsor's written procedures. More frequent revision may be appropriate depending on the stage of development and the generation of relevant new information. However, in accordance with GCP relevant new information may be so important that it should be communicated to the investigators, and possibly to the (IECs and/or regulatory authorities before it is included in a revised IB. Given this, the IB has to be revised annually even if there are no safety updates with a mention of the same.

What are the labelling requirements for clinical trials in India?

Dr Sunita Vashishtha

The labelling for clinical trials is as per relevant GMP requirements. However, we accept the labels as per International labels for clinical trials. Indian GCP has given a format
2.3.1.6. Handling of the Product(s)

Measures to be implemented to ensure the safe handling and storage of the pharmaceutical products.
System to be followed for labelling of the product(s) (code numbering etc.)
The label should necessarily contain the following information: the words - “for clinical studies only”, the name or a code number of the study, name and contact numbers of the investigator, name of the institution, subject’s identification code.

However, name and contact numbers of the investigator is not given as this practically difficult.

Kindly advise us whether we require DCGI or Ayush approval for conducting a post-market clinical trial on an ayurvedic product. And please advise us whether it is mandatory to register such trials with CTRI.

Ajay Jagan

Ayush GCP guideline defines Phase IV as follows:
Phase IV: Studies performed after marketing of the ASU medicine / other TM. Trials in phase IV are carried out on the basis of the product characteristics on which the marketing authorization was granted and are normally in the form of post-marketing surveillance, assessment of therapeutic value, treatment strategies used and safety profile. Phase IV studies should use the same scientific and ethical standards as applied in pre-marketing studies.

After a product has been placed on the market, clinical trials designed to explore new indications, new methods of administration or new combinations, etc. are normally considered as trials for new ASU medicines / TM.

ICMR 2006 recommends phase IV - The phase IV studies should have valid scientific objectives. After approval of the drug for marketing, phase IV studies or post marketing surveillance is undertaken to obtain additional information about the risks and benefits resulting from long term usage of drug. It is an important aspect of drug trial on the long-term effects of the drugs and the adverse reactions induced by drugs, if any, should be brought to the notice of the Ethics Committee. There is a need to correlate the adverse events reported during phase IV trials with the toxicity data generated in animals, to draw markers for future warnings of potential adverse events likely to occur with other drugs. These trials may not be necessary for approval of new drug for marketing but may be required by the Licensing Authority for optimizing its use.

These studies also include those on specific pharmacologic effect, drug-drug interaction(s), dose-response studies, trials designed to support use under approved indication(s) e.g. mortality/morbidity studies, clinical trials in a patient population not adequately studied in the pre-marketing phase, e.g., children; and epidemiological studies etc. Bioequivalence and bioavailability study also falls under this category.
In addition there are phase IV studies that are designed to evaluate the marketed drug in specifically designed studies, which have inclusion/exclusion criteria, objectives and end points. The drug is used for the labelled indication in these studies. Therefore Licensing Authority permission is not needed. However, EC permission is needed.

A third type of post-marketing study involves evaluation of the drug for a new indication of a marketed drug, e.g. studies with letrazole. Here, DCGI permission and EC approval are needed which really makes the trial a Phase III study.

If the objective of post-marketing clinical trial is to assess safety of the formulation, no regulatory approval is needed. However, if the study is a clinical trial in a new indication, regulatory permission is needed. For herbal products, the regulatory issues are reviewed by Department of Ayush.

Source: Pharmabiz

Health ministry upgrades CTRI with new features to cope with momentum in registration

2011-03-25T03:32:00.000-07:00

In order to cope up with the momentum in registration of clinical trials in the country which has been picking up fast ever since registration of clinical trials was made mandatory by the DCGI from June 15, 2009, the Union Health Ministry has upgraded the Clinical Trial Registry of India (CTRI) with several new features.

In the upgraded version, the CTRI has incorporated new features on audit trial, submission of EC-DCGI approval documents, trial transfer, trial search, etc.

In the new software application, once a trial is registered, all fields would be automatically 'locked' except for 'Recruitment status of trial'. In case changes are desired to be made, request has to be sent to the CTRI, quoting CTRI registration number, indicating the field that is to be changed. Accordingly, only the desired field will be 'unlocked' and once changes have been incorporated, the field will again become 'locked'. Further, all these changes will be available for public view, under 'Modifications' when a trial is viewed in the public domain. Uploaded documents if any are not visible in the public domain, although registrant may be able to view it upon login to CTRI.

For pre-registered trials, all fields remain unlocked except for those trials where Ethics Committee and DCGI approvals have been obtained. Registrants are encouraged to upload any additional information according to the new data. However, these changes will also be visible in the public domain under 'Modifications.'

As per the upgraded version, EC-DCGI approval documents may now be uploaded from the CTRI site itself. The uploaded documents will not be visible in the public domain. It is now feasible to transfer a trial from one registrant to another, within a company or between companies. Besides, trials can be searched and viewed by using a single word search (keyword search) or specific field search (advanced search) or a layered search (trial search).

The Clinical Trial Registry of India was introduced by the government in July 2007 as part of its exercise to strictly regulate the clinical trial industry in the country. The National Institute of Medical Statistics (NIMS), an arm of the Indian Council for Medical Research (ICMR) was mandated with the responsibility of setting up and maintaining the CTRI.

Based on the experience of the pilot project, it was decided to implement a fresh well designed Web Hosted Clinical Trial Registry to meet the expectations of the various stakeholders including the pharmaceutical industry, researchers, publications, administrators and the public at large. Being a front runner, among the first 10 across the world, in the implementation of the mandate of registration of clinical trials, the Clinical Trial Registry of India is being keenly monitored across the world.

Source: Pharmabiz

Vidya Sury

If it feels good, do it!

Evidence for Atypical Antipsychotic Drugs Called into Question

2011-01-13T00:17:00.000-08:00

Despite massive advertising and booming prescriptions, use and sales, the new atypical antipsychotic medications such as Seroquel and Abilify – used to treat schizophrenia, bipolar disorder, depression and other illnesses – lack sufficient evidence to support their widespread and generalized usage. This according to a new study out of the Stanford University School of Medicine and University of Chicago.

In the past decade, atypical antipsychotics have rocketed past many commonly prescribed, but older antidepressant and other psychiatric medications. Although initially touted as having few side effects, followup studies have found that atypical antipsychotics have serious side effects, including significant weight gain that can lead to diabetes and heart disease.

“Because these drugs have safety issues, physicians should prescribe them only when they are sure patients will get substantial benefits,” said Randall Stafford, M.D., Ph.D., a Stanford associate professor of medicine and senior author of the new study.

The new research analyzed the results of a physicians’ survey conducted by health-care information company IMS Health. The IMS Health National Disease and Therapeutic Index survey gives a snapshot of the conditions doctors treated and drugs they prescribed. About 1,800 physicians participate each calendar quarter and each is randomly assigned two days per quarter to provide data.

After identifying which antipsychotics were being used, and for what, the researchers assessed the strength of the evidence supporting those that lacked FDA approval, using efficacy ratings from the widely used drug compendium, Drugdex.

The researchers found that:

Antipsychotic treatment prescribed during the surveyed doctors’ visits nearly tripled from 6.2 million in 1995 to 16.7 million in 2008, the most recent year for which they had data. During this period, prescriptions for first-generation antipsychotics decreased from 5.2 million to 1 million.
Antipsychotic use for indications that lacked FDA approval by the end of 2008 increased from 4.4 million prescriptions during surveyed doctors’ visits in 1995 to 9 million in 2008.
In 2008, more than half — 54 percent — of the surveyed prescriptions for the new-generation antipsychotics had uncertain evidence.
An estimated $6 billion was spent in 2008 on off-label use of antipsychotic medication nationwide, of which $5.4 billion was for uses with uncertain evidence.
Prescriptions for antipsychotics began dropping slightly in 2006, shortly after the FDA issued a warning about their safety.

Prescriptions for these drugs have risen steadily since they first came on the U.S. market in 1989, largely replacing the first generation of antipsychotics, which were mainly used to treat schizophrenia.

The U.S. government’s original stamp of approval for the new drugs was for treating schizophrenia, but they’re used more today for other conditions, including other psychoses, autism, bipolar disorder, delirium, dementia, depression and personality disorders. And while some of these uses have recently been approved by the U.S. Food and Drug Administration (FDA), many have not.

For example, the FDA has approved quetiapine (Seroquel), the antipsychotic with the biggest U.S. sales, for treating schizophrenia and some aspects of bipolar disorder and depression. But the drug is also often used for the treatment of other mental health concerns, such as anxiety and dementia. This kind of use that hasn’t been specifically approved by the FDA is called “off label” prescribing, because a doctor is prescribing the drug for an indication not on the drug’s label.

These new drugs accounted for more than $10 billion in retail pharmacy U.S. prescription drug costs in 2008, representing the largest expenditure for any single drug class — nearly 5 percent of all drug spending, surpassing even blockbusters like statin cholesterol medications. According to a 2004 study, a quarter of all residents of U.S. nursing homes had taken them. Among the drugs are quetiapine, aripoprazole (Abilify), olanzapine (Zyprexa) and risperidone (Risperdal), each with annual U.S. sales exceeding $1 billion.

Stafford’s new study adds to concerns about the drugs, which have been the focus of thousands of lawsuits, and as a class make up the single largest target of litigation filed under the federal False Claims Act. All major companies selling new-generation antipsychotics have either recently settled cases for hundreds of millions of dollars or are currently under investigation for skewing results or using questionable marketing tactics.

In 2005, the FDA issued its strongest type of caution, the “black box” warning, for use of new-generation antipsychotics, because of increased risk of death for dementia patients.

“Most people think, ‘If my doctor prescribed this, the FDA must have evaluated whether this drug was safe and effective for this use.’ That’s not true,” said Stafford. When doctors prescribe drugs for purposes other than those approved by the FDA, it’s called “off-label” use. Though it’s riskier for patients, there’s nothing illegal about it, and can make sense medically in some instances, Stafford said, especially if there are no approved treatments or if a patient has not responded to approved drugs.

Previous studies had shown that antipsychotic drug use is ballooning. Stafford’s new study not only corroborated and updated these findings but also identified the fraction of off-label use that is based on uncertain evidence.

Lead author Caleb Alexander, M.D., assistant professor of medicine at the University of Chicago, and colleagues conducted the analysis. Stafford supervised the project and Alexander interpreted the data. Stanford clinical assistant professor of psychiatry Anthony Mascola, M.D., provided expertise on the treatment of psychiatric conditions.

Stafford suggests the upswing in prescriptions for antipsychotics despite the absence of good evidence for their value in many instances is the result of marketing — whether legal or illegal — and ingrained cultural tendencies. “Physicians want to prescribe and use the latest therapies — and even when those latest therapies don’t necessarily offer a big advantage, there’s still a tendency to think that the newest drugs must be better,” he said.

Physicians could benefit from more feedback on what percentage of their prescriptions is for off-label uses, said Stafford. “In many cases, physicians don’t realize they’re prescribing off-label,” he said.

In fact, in a previous survey of physicians, Alexander found that the average respondent accurately identified the FDA-approval status of drugs for a given condition just over half the time.

A number of psychiatrists and other commentators have been critical of the push by pharmaceutical companies to expand the use of atypical antispychotics beyond its application to schizophrenia. As Daniel Carlat, M.D., wrote in his widely read Carlat Psychiatry Blog, “Why approve an antidepressant that causes weight gain, diabetes, and cardiac death, when there are equally effective alternatives that cause none of these side effects?”

The new study is published online in the Jan. 7 issue of Pharmacoepidemiology and Drug Safety.
Source: Stanford University Medical Center

Article source: Psychcentral

Merry Christmas!

2010-12-24T07:33:00.001-08:00

May the holidays be filled with fun,
laughter, health and happiness!

Love and Peace!

Vidya Sury

Shri Arun Madhavan speaks

2010-12-20T00:13:00.000-08:00

Shri Arun Madhavan's talk at Purna Pragnya. He speaks of what the children of Purna Pragnya must feel when they leave after finishing their studies. He gives a glimpse of the fundamentally simple meaning of our life.

Sanofi Pasteurs dengue vaccine in ph III clinical trials

2010-11-09T19:43:00.000-08:00

News item: Source BioSpectrum, Asia Edition


Singapore, Nov 4, 2010: Sanofi Pasteur, the vaccines division of Sanofi-aventis Group, has announced that its dengue vaccine is in final stage of clinical development. Sanofi Pasteur’s dengue vaccine, the world’s most clinically advanced dengue vaccine candidate entered its first phase III clinical study in Australia. This study is part of a global phase III clinical study program aimed at advancing the development of a novel vaccine for the prevention of dengue disease in children and adults. Currently, there is no specific treatment available for dengue fever, which is a threat to nearly three billion people and a public health priority in many countries of Latin America and Asia where epidemics occur. Phase III studies are the ultimate steps in the clinical development of a vaccine before it is submitted to regulatory authorities for evaluation for market authorization. Sanofi Pasteur’s candidate dengue vaccine is the first to reach phase III of clinical development. “To address the global health challenge represented by dengue fever, we are conducting an unprecedented dengue vaccine research and development program as well as a scale up of the vaccine production. We are now entering the final laps of a long run that Sanofi Pasteur started almost 20 years ago. If successful, we are committed to introducing the vaccine in countries where dengue is of highest public health priority,” said Mr Wayne Pisano, President and Chief Executive Officer of Sanofi Pasteur. The study in Australia is the first to use dengue vaccine doses produced with industrial scale processes. The study is aimed at demonstrating that production of the vaccine at industrial scale will meet consistency criteria required for market authorization by regulatory authorities. Details of the phase III study in Australia as well as results of already completed studies are presented at the 59th annual conference of ASTMH (American Society of Tropical Medicine and Hygiene), held in Atlanta, US, on November 3-7, 2010.

Fentanyl transdermal pain patches recalled

2010-11-02T07:34:00.001-07:00

After tests revealed too-rapid release of active ingredient about one million fentanyl patches for chronic pain have been recalled from store and pharmacy shelves.

Approximately one million fentanyl patches for chronic pain have been recalled from store and pharmacy shelves. The U.S. Food and Drug Administration and drug maker Actavis Inc. are working to get the word out, but they are targeting retailers and wholesalers, not consumers.

Continue reading

FDA Restricts Use of Diabetes Drug Avandia

2010-09-23T21:03:00.000-07:00

FDA Decides Not to Ban Avandia, but Puts Restrictions on How It’s Used.
By Daniel J. DeNoon
WebMD Health News

Sept. 23, 2010 -- The FDA will not ban Avandia -- but stringent restrictions will make it far harder for doctors to prescribe the safety-troubled diabetes drug.

The European Medicines Agency took harsher action. European sales of Avandia-containing drugs will be suspended over the next few months, although the agency did not formally withdraw approval.

The 600,000 U.S. patients currently taking Avandia can continue to take the drug only if their doctors officially attest that their patients understand the risks, that the drug is helping them, and that no other diabetes drug can keep their blood sugar under control.

New Avandia prescriptions can only be written for patients who, for medical reasons, cannot take Actos. Actos, a diabetes medication in the same class as Avandia, does not cause the heart problems linked to Avandia.

"Avandia will be available to new patients only if they cannot achieve [blood sugar] control on other agents and cannot take Actos," FDA commissioner Margaret A. Hamburg, MD, said at a news conference. "Current patients can continue taking Avandia only if they benefit and understand the risks."

Avandia maker GlaxoSmithKline will be required to establish a Risk Evaluation and Mitigation Strategy (REMS) program. Patients, their doctors, and their pharmacists will have to enroll in the program in order to receive, prescribe, or sell Avandia.

Avandia Heart Risks Clouded by Uncertainty

Hamburg admitted that FDA experts are split over how to interpret the scientific evidence suggesting that Avandia damages the heart. Both Avandia and Actos increase the risk of heart failure. But evidence suggests that only Avandia increases risk of heart attack.

Janet Woodcock, MD, director of the FDA's Center for Drug Evaluation and Research, noted that an FDA advisory panel last July split over the issue of whether the evidence proved Avandia unsafe.

"In and outside the agency there is mostly agreement on the facts, but not on the weight of the safety analysis," Woodcock said at the news conference. "This has resulted in different conclusions, not only inside FDA but among outside experts. This reflects uncertainty in the science that tells us whether or not Avandia causes these problems."

Questions about Avandia heart safety should have been answered by the RECORD study, which Avandia maker GlaxoSmithKline conducted at the behest of the European drug agency. This study found Avandia to be safe, but critics have lambasted the study's poor design. Moreover, an FDA analysis suggests that the study failed to investigate all possible heart attacks in study patients.

Today's FDA action will require GlaxoSmithKline to convene a panel of independent scientists to review the RECORD data. That review may cause the FDA to lift the new Avandia restrictions -- or to ban the drug.

The FDA today also officially ended a study called TIDE, which was directly comparing Avandia and Actos. The FDA decided that the study, which already had been suspended, posed too much risk to participants.

In a statement, GlaxoSmithKline says it "continues to believe that Avandia is an important treatment for patients with type 2 diabetes," but that it will work with the FDA and the European Medicines Agency to implement their decisions.

Thank you, WebMD

Gilenya, First Oral MS Drug, Gets FDA Nod

2010-09-22T19:11:00.000-07:00

Once-Daily Capsules Cut MS Relapses, Delay Progression

By Daniel J. DeNoon
WebMD Health News

Sept. 22, 2010 -- The FDA today approved Novartis' Gilenya, the first oral drug for multiple sclerosis (MS). Gilenya (formerly spelled Gilenia, generic name fingolimod) last June received the overwhelming approval of an FDA expert advisory panel.

Gilenya treats the relapsing form of MS. The drug significantly reduces MS attacks. However, it has serious side effects, with possible heart, lung, and eye toxicity and increased risk of infection. Patients must be closely monitored, and regular eye exams are advised.

In MS, white blood cells attack the myelin sheaths that protect nerve cells. Gilenya, the first drug in its class, keeps white blood cells penned up in lymph nodes by taking away the chemical key they need to unlock the lymph node door.

Fewer white blood cells mean fewer MS attacks. But it also means less protection against infections. Novartis will set up a careful program for educating and monitoring patients taking the drug. Moreover, the company will continue long-term studies to look for side effects that may occur with longer-term use.

Gilenya was invented as a new way to prevent rejection in kidney transplant patients. But at the necessary dosage, the drug was far too toxic. The dose that would be used to treat MS is five times lower than the lowest dose tested in the transplant studies.

Even at this dosage, Gilenya can have severe toxicity. In clinical trials, side effects linked to Gilenya included:

    * Elevated liver enzymes
    * Macular edema (swelling of the central portion of the retina, causing distorted vision)
    * Elevated blood pressure
    * Shortness of breath
    * Bronchitis
    * Diarrhea
    * Bradycardia (slowing of the heartbeat, seen only upon first treatment. The FDA panel recommended that patients be required to receive their first dose under medical supervision).

Two fatal herpes infections occurred in MS patients treated with Gilenya at 2.5 times the 0.5-milligram dose for which Novartis is seeking approval.

But overall, the drug's benefits outweighed its risks among the more than 2,600 MS patients who took the drug in clinical trials.

How overdose of paracetamol hits kids

2010-08-08T02:49:00.000-07:00

“Anxious mothers are feeding children excessive dosages”

“Overdose can happen more easily in children”

‘Drops' version mistaken for syrup

Even love is valuable only if it is given in the right dosage. Overdoses of drugs, specially the common paracetamol, need not be dangerous in adults, but can lead to serious complications, including liver failure, in children.

Over the past few weeks, with viral and flu infections rampant, a number of children have been admitted to the intensive care units, not for treatment of the primary illness, but for paracetamol poisoning. Janani Sankar, senior consultant, Kanchi Kamakoti CHILDS Trust Hospital, says kids come in with multi-organ failure, and while most of them could be saved, some have been beyond help as they have come too late.

“Two types of overdosing can occur: one is accidental, when the children drink up syrup because it is tasty; or two doses are taken by mistake. The other is what we are commonly seeing now: mothers with extreme anxiety feeding their children excessive dosages of paracetamol in order to bring the fever down,” Dr. Janani adds.

In a season when dengue cases are numerous, the course of the disease itself involves very high fever for several days. Mothers, in their anxiety to reduce the fever end up giving more than the recommended dosage, she says.

“In children, paracetamol overdosing can happen more easily than in adults. Doses are calibrated with body weight, and in children, even a little extra may be too much,” P. Ramachandran, director, Institute of Child Health, says. He adds that a number of private hospitals are reporting such cases increasingly.

Different values

Parents sometimes do not check the dosage of the drugs they are giving the child, as they are available in different values across different brands.

“There is the Double Strength version which they buy instead of the regular dose. With the increase in the number of dosages per day, the chances that it becomes too much for the child is high,” Rex Sargunam, senior paediatrician, explains.

Yet another complication arises because parents sometime mistake the ‘drops' version for the syrup. Deepa Hariharan, neonatologist at Sooriya Hospital says, “We had two cases recently of really sick children, where parents had bought drops instead of syrup.”

In the drops, there is 100 mg of drug in one ml while with the syrup, there is 125 mg in five ml.

“When we ask the parent to give 5 ml of the syrup four times a day, we intend a dose of 500 mg. Instead the parent buys the drops, and lands up dosing the child with 2000 mg of paracetamol,” Dr. Deepa adds.

In children, the liver is not very mature and therefore this overdose can be dangerous.

Dr. Janani cautions parents, “Do not be extraordinarily anxious and overdose the child. The paediatrician's recommended dosage must be stuck to at all times.”

Dr. Ramachandran also adds that parents and physicians should suspect and look for signs of paracetamol poisoning when a child is ill. “Initially there will be vomiting, maybe with some blood, the child will feel drowsy and will have liver damage within one to three days. Parents and physicians should watch out for this,” he says.

Laboratory tests to confirm unacceptable paracetamol levels are available and once the diagnosis is confirmed, treatment can be started at once.

This article is from The Hindu

''Dynamic Indian of the millenium"

2010-07-05T06:20:00.000-07:00

As Member Secretary of CLINICOM, I am so thrilled to post this information here:

''Dynamic Indian of the millenium" award conferred

Coimbatore, Jul 4 (PTI) City-based K G Foundation today conferred the 'Dynamic Indian of the Millennium' award on Arun Madhavan, a former member of Prime Minister's special committee for model village development programme under the 20-point programme.

The award, carrying a citation, was given for his 'distinguished achievements and contribution to society over the years', the foundation chairman G Bhakthavatsalam, said at a function got up as part of the celebrations of World Doctors' Day, here.

Besides being conferred a global recognition for his 'project gateway' for promoting India as an investment destination, Arun had delivered a speech at the United Nationas, Geneva, on 'A New dimension to healthcare,' in 1996, he said. The first recipient of this award was the former president, A P J Abdul Kalam, a decade ago.

Note: The members of CLINICOM are applauding. Our best wishes are with Sri Arunji, always.

Stem cell scientists warn against fraudulent treatments

2010-07-05T02:04:00.001-07:00

A new website will help people decide which therapies are safe and effective.
By Sandy Kleffman, Contra Costa Times

Leading scientists are warning people to beware of costly, unproven stem cell therapies that have little or no benefit and may be dangerous.

Many with devastating illnesses are mortgaging their homes and borrowing huge sums of money for treatments, which are often performed outside the United States to avoid its safety regulations.

Scientists worry that such therapies could harm people by leading to cancers and other complications.

"It's really the 21st century version of snake oil," said Dr. Arnold Kriegstein, director of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UC San Francisco.

"As soon as you scratch the surface, you realize that what they're claiming in their literature or what they tell you about, doesn't make sense," he said. "There's this notion that stem cells are in some way magic cells that can treat anything if you just deliver them into the body. That's pseudoscience and make-believe."

Stem cells have captured worldwide attention because of their ability to renew and form new cells. Scientists hope such cells can one day cure a host of deadly diseases by replacing injured and dying cells.

Of particular interest are embryonic stem cells, which can transform into virtually any cell type in the body.

But despite the encouraging signs, scientists are in the early stages of research. To date, only a handful of stem cell treatments have proven safe and effective in clinical trials. These include bone marrow transplants to treat lymphomas and leukemias, or to replace bone marrow destroyed by high doses of chemotherapy during cancer treatments.

Other well accepted therapies involve skin grafts and corneal repair.

But it can be difficult for people to determine which treatments are backed by scientific evidence. Searching the Internet for stem cell therapies will yield more than 200 companies claiming they can cure almost any condition by growing stem cells and injecting them into a patient.

"Once you read those websites and see what they are doing to people, you begin to lose faith in human nature," said Dr. Irving Weissman, director of the Stanford Institute for Stem Cell Biology and Regenerative Medicine, in a written statement. "They will take the last dollars and days of people's lives."

Weissman co-authored a report about the risks published in this week's edition of Cell Stem Cell.

The excitement surrounding stem cell research "has led to unacceptable exploitation of patients' hopes and fears," the report states.

As the immediate past president of the International Society for Stem Cell Research, Weissman convened a task force that oversaw the creation of a website to educate the public about stem cell research and to help people decide whether treatments are effective and safe.

The site, at www.closerlookatstemcells.org, recommends questions to ask before receiving a treatment.

People can also request that the stem cell society investigate a company or clinic. The society will attempt to determine whether a medical ethics committee is involved to protect patients' rights and whether the treatment will be supervised by an official regulatory body such as the U.S. Food and Drug Administration or the European Medicines Agency.

The results will be posted on the website, although it may take four or five months to complete the review.

In addition to protecting the public, stem cell researchers want to avoid having the fraudulent clinics cast a shadow over stem cell research or cause the public to question legitimate breakthroughs.

Scientists still have much to learn about stem cells, including how to ensure that embryonic stem cells transform into a specific cell type.

Worrisome results
One big concern is that stem cells will start producing tumors or cancers during untested treatments, Kriegstein said.

He noted that this happened with a boy in Moscow who developed tumors in his central nervous system as a result of a therapy.

Another worry is that a patient's body could reject the stem cells.

"These cells usually come from one or more donors that are not related to the patient and haven't been in any way matched, so they run the risk of having immune responses that could be significant," Kriegstein said.

It can be risky even to use a patient's own stem cells, the website notes. After the cells are removed from the body, they could become contaminated with bacteria or viruses that cause diseases when they are injected back into the body. If they are grown in a culture, they may lose the normal mechanisms that control growth or may lose the ability to specialize into the cell types the patient needs

Kriegstein said he understands that patients who seek such treatments often have no options. But because of the problems, he said, "I think going to these places is worse than having no treatment at all."

Among the suggested questions for people to ask is the source of the stem cells and how they are isolated and grown.

"Be wary of clinics that offer treatments with stem cells that originate from a part of the body that is different from the part being treated," the website notes. Stem cells from bone marrow regenerate blood, for example, but cannot make brain cells.

Kriegstein urges people to question how stem cells will be delivered to the right part of the body. Stem cells injected into one area may not make it to the area that needs repair, "let alone actually do something once they get there," he said.

Breakthroughs expected

Despite such cautions, Kriegstein and others are convinced the future is bright for stem cell research. Companies and scientists in the Bay Area and elsewhere are striving for scientific breakthroughs and are increasing their knowledge about how such cells work.

The first embryonic stem cell treatment for acute spinal cord injury is under review by the FDA and may soon move into clinical trials.

And in February, the British company ReNeuron announced it had been approved for a clinical trial of a stem cell treatment for strokes.

"We and others around the world are working very hard, as quickly as we can, to test therapies and develop new approaches," Kriegstein said.

"Eventually, I have complete faith that there will be therapies available that will come out of the current research that's going on in stem cell biology, but it will take time," he said. "There are certain disease areas where it may happen sooner than others. But the potential of stem cells is certainly there."

Questions to ask

The International Society for Stem Cell Research has set up a website to help people decide if treatments are effective and safe, at www.closerlookatstemcells.org People can ask the society to review a clinic, although it may take four to five months for a response.

Here are some questions for patients to ask:

What is the source of the stem cells? How are they isolated and grown?
How are the cells delivered to the right part of the body?
How will my immune system be prevented from rejecting these cells?
What is the scientific evidence that this could work for my disease or condition?
What are the risks?
Is a medical ethics committee involved?
Is there supervision by a regulatory body such as the U.S. Food and Drug Administration or European Medicines Agency?

Source: International Society for Stem Cell Research

Smoking parents = fat, bad kids

2010-07-01T23:57:00.001-07:00

Two new studies suggest there's a connection between parents who smoke and kids who are heavier or misbehave more than other children.

The researchers haven't definitively proven that lighting up puts kids at risk for bad behaviour and extra pounds. In fact, it may be impossible to ever prove a cause-and-effect because it's considered unethical to assign some parents to smoke and then see what happens.

Still, the findings "tighten the link" between parents who smoke and physical and mental health problems in their kids, said Dr Jonathan Winickoff, an associate professor of pediatrics at Massachusetts General Hospital, who co-wrote a commentary accompanying the research.

For decades, doctors have advised pregnant women to avoid smoking for fear that they would harm their unborn children; research has linked smoking in mothers to physical problems in offspring such as low birth weight. If the mother smokes during the first trimester, the effects are worse than in later trimesters, said Neil E. Grunberg, a professor of medical and clinical psychology at the Uniformed Services University of the Health Sciences, in Bethesda, Md.

But it hasn't been as clear whether there's a connection between mothers who smoke and other health problems in their kids. And the influence of fathers who smoke - exposing their kids to secondhand smoke or perhaps affecting sperm at conception - has also remained a mystery.

The study

In one of the new studies, researchers examined what happened to kids whose fathers smoked but their mothers did not. Researchers from the University of Hong Kong studied 7,924 kids from that region who were born in 1997.

The researchers found that the kids who had fathers who smoked were more likely to be heavier at ages seven or 11 after the statistics were adjusted so they wouldn't be thrown off by factors such as gender and socioeconomic status.

The study appears in the July print issue of Paediatrics, as does a study linking pregnant mothers who smoke to misbehaving kids.

The second study

In that second study, British and Brazilian researchers studied 509 children in Brazil and 6 735 in England. After adjusting their statistics to account for possible confounding factors, they discovered that kids of mothers who smoked while pregnant were more likely to be deemed aggressive and disruptive.

This isn't the first time researchers have come to this conclusion, said Grunberg. And if smoking does cause the problems, the study doesn't say how, he added.

So, what might be the connection between parents who puff cigarettes and kids who misbehave and weigh more than others?

Winickoff, co-author of the commentary, said it's not true that smoking makes people skinnier. Instead, it boosts the weight around their bellies and hips, he explained. One theory is that secondhand smoke could do the same thing to those who are exposed, like the kids of dads who light up.

As for pregnant mothers who smoke, their bodies don't act as filters, he said. Instead, the toxins from smoking affect the foetus.

"Anyone who's been in the delivery room when a mother who smokes cigarettes delivers can attest to the state of the placenta," he explained. "In general, it's withered, discoloured. It's very clear that the blood supply to the child is compromised." - (HealthDay News, June 2010)

Rosiglitazone - increased risk of myocardial infarction?

2010-07-01T23:50:00.001-07:00

NEW YORK (Reuters Health) - Two reports today in two separate journals -- a meta-analysis and a large retrospective study -- provide more evidence linking the thiazolidinedione rosiglitazone to an increased risk of myocardial infarction (MI).

The retrospective study also ties rosiglitazone therapy to an increased risk of stroke, heart failure, and death from any cause in patients aged 65 and older.

In an e-mail to Reuters Health, Dr. Steven E. Nissen, chair of the Department of Cardiovascular Medicine at The Cleveland Clinic and a long-time vocal critic of rosiglitazone, said the two manuscripts "provide overwhelming evidence of the hazards" of the drug.

"Taken together," he wrote, "the two studies demonstrate that this drug has an adverse benefit risk relationship and should be removed from the market. I would advise physicians who are still using rosiglitazone to stop and begin switching their patients to safer alternatives, including pioglitazone."

Concern over the effects of rosiglitazone on the heart arose in 2007 after Dr. Nissen and colleagues published a meta-analysis that showed a significantly elevated risk of MI and a borderline significant increased risk of cardiovascular death with its use.

Today, in the Archives of Internal Medicine, Dr. Nissen and co-author Kathy Wolski, also of the Cleveland Clinic, report results of an updated meta-analysis of 56 randomized controlled trials published through February 2010. These trials lasted at least 24 weeks and included a total of 35,531 patients; 19,509 received rosiglitazone and 16,022 received comparator drugs or placebo. (The journal has made the full text of the article available for free; the link appears below.)

There was no evidence from the updated meta-analysis that rosiglitazone increases the risk of cardiovascular deaths or all-cause mortality.

However, the authors estimate there is a 28% to 39% increased risk of MI with rosiglitazone, with a number needed to harm of 52 with RECORD trial data included and 37 without this trial. (Low event rates in the open-label, noninferiority RECORD trial of rosiglitazone published in 2009 resulted in insufficient statistical power to confirm or refute evidence of increased risk for MI).

Subgroups classified by study length and comparator drug used also showed elevated risks with rosiglitazone. "These findings are consistent with prior meta-analyses conducted by GSK (GlaxoSmithKline), the FDA, and most independent investigators demonstrating an increased risk of MI in patients treated with rosiglitazone," Dr. Nissen and Ms. Wolski note in their report.

"Because no unique benefits of rosiglitazone use have been identified," they add, "administration of this agent solely to lower blood glucose levels is difficult to justify."

The second paper, published in the Journal of the American Medical Association by Dr. David J. Graham, of the FDA's Center for Drug Evaluation and Research in Silver Spring, Maryland, and colleagues, reports the results of a large US cohort study examining the risk of cardiovascular events in 227,571 patients aged 65 and older. These patients initiated treatment with either rosiglitazone or pioglitazone between 2006 and 2009 and were followed for up to three years. (This paper too is available online at no charge from the journal; the link appears below.)

There were 8,667 events during the study period. Compared with pioglitazone, rosiglitazone was associated with an increased risk of adverse cardiovascular events, including heart failure (odds ratio, 1.25), stroke (OR, 1.27), death (OR, 1.14), and the composite of acute MI, stroke, heart failure or death (OR, 1.18).

Notably, the authors say the attributable risk for the composite endpoint was 1.68 and the number needed to harm was 60 treated for 1 year.

"The Graham study is well done and large," Dr. David N. Juurlink, author of an editorial in JAMA, told Reuters Health by e-mail, "and it adds to the evidence that rosiglitazone is less safe than pioglitazone."

"I think that was pretty clear before the Graham paper, but this new study throws another log on the fire at the feet of the FDA," added Dr. Juurlink, of Sunnybrook Health Sciences Center, Toronto, Canada.

The US FDA will hold an advisory committee meeting in July to consider whether to remove rosiglitazone from the market.

Reference
http://archinte.ama-assn.org/cgi/content/full/2010.207 http://jama.ama-assn.org/cgi/content/full/jama.2010.920 http://jama.ama-assn.org/cgi/content/full/jama.2010.954

Arch Intern Med 2010.
JAMA 2010.