Thursday, December 1, 2011

Indian trial compensation guidelines open to comment

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

Continue reading here:
Indian trial compensation guidelines open to comment

Thursday, November 3, 2011

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

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.


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.

Sunday, October 23, 2011

Compensation package for clinical trial victims in the offing

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".

Thursday, October 20, 2011

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

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.

Friday, October 14, 2011

BE guidelines regarding investigator

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.

Friday, August 19, 2011

In India, there is no separate guidance on pregnancy reporting

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?

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).

Thursday, June 9, 2011

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

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

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.

Thursday, May 12, 2011

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

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?  

Friday, April 15, 2011

EC chairperson can serve as legal expert during the meeting

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.

Monday, April 11, 2011

Good Clinical Practices

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.


Friday, March 25, 2011

Registration of herbal trials in CTRI is not mandatory

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?

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

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.'

Thursday, January 13, 2011

Evidence for Atypical Antipsychotic Drugs Called into Question

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: