Post-marketing safety depends on the objective
Thursday, December 03, 2009 08:00 IST
Dr Arun Bhatt
We are doing one clinical trial in that serious adverse event occurred after completion of study period. What we should do?
Raghu
It would be desirable to report this event to the sponsor. It also should be reported to ethics committee, and regulatory agency after causality and expectedness are assessed. See ICH guidance below.
ICH E2A 3. Post-study events
Although such information is not routinely sought or collected by the sponsor, serious adverse events that occurred after the patient had completed a clinical study (including any protocol-required post-treatment follow-up) will possibly be reported by an investigator to the sponsor. Such cases should be regarded for expedited reporting purposes as though they were study reports. Therefore, a causality assessment and determination of expectedness are needed for a decision on whether or not expedited reporting is required
For bioequivalence study of an anticancer agent, is it necessary to dose all the subjects in one single day?
Rendeep Rajendran
There is no regulatory requirement to dose all the subjects in one single. As anticancer drugs usually cause adverse events, it would be desirable to take small cohorts of patients.
Many of the Institutional Ethics Committee do not clearly mention reporting annual status/progress report during the course of study. What are the steps to be taken for this situation especially when you are looking forward to select this site because PI is good/experienced investigator and site infrastructure complies with the current study requirement?
Deepu
ICH GCP mandates that IEC should review the project at least once a year. Indian GCP recommends that IEC has the responsibility of continuing review. Schedule Y EC approval recommends that EC letter mention that EC expects to be informed of the progress.
ICH GCP 3.1.4 The IRB/IEC should conduct continuing review of each ongoing trial at intervals appropriate to the degree of risk to human subjects, but at least once per year.
3.3.3 Conducting initial and continuing review of trials.
Schedule Y
The Institutional Ethics Committee / Independent Ethics Committee expects to be informed about the progress of the study, any SAE occurring in the course of the study, any changes in the protocol and patient information / informed consent and asks to be provided a copy of the final report.
Indian GCP
The Ethics Committees are entrusted not only with the initial view of the proposed research protocols prior to initiation of the projects but also have a continuing responsibility of regular monitoring for the compliance of the Ethics of the approved programmes till the same are completed.
It is necessary to bring to the notice of investigator / EC about this requirement and to request that their SOP cover this requirement for annual review.
Kindly let me know whether can we use comparator in Post Marketing Surveillance study. What is the necessity to use comparator after regulatory approval to market the product?
Raghu
The PMS design depends on the objective. If the objective is to assess post-marketing safety of a new drug, comparator is not required. However, if the objective to assess efficacy vis-a-vis other therapy/new therapy on the market and to support marketing claims, a comparator is usually required
Are any foreign reports for the same product (marketed in India) required by DGCI?
Niharika Mathur
Please check the DCGI approval letter. It does not clearly state - local or foreign reports. As a practice, most foreign companies in India send local reports only.
Are local expected events reportable?
Niharika Mathur
As a convention all post-marketing events are considered drug related and are reported to DCGI
Which cases should be included in the PSUR?
Niharika Mathur
All cases - local / foreign - will be in PSUR.
As per Indian GCP sub-investigator & co-investigator are synonymous
Thursday, January 07, 2010 08:00 IST
Dr Arun Bhatt
Our Neurosurgeon wants to participate in a surgical trial sponsored by an international not-for-profit institute. The investigators are recruited through the trial website. Trial objective is primarily to compare early vs. late interventions intra-cerebral hemorrhage. There is no financial involvement in the trial; no agreements, no indemnity and no insurance.
The issues are:
a) Can take place without the approval of a regulatory body in India considering the trial sponsor is based outside the
country?
b) Which regulatory framework should Ethics Committee use to evaluate such studies?
c) Will CTRI registration be required and if so, is it
the investigator's responsibility?
d) Can data emanating from Indian sites (Indian patients) be shared with any regulatory approvals?
e) How about subject protection in case of injury because of delayed surgery?
Dr. Sumeet Roy
Regulatory and ethics issues:
As the study does not involve a new drug or device, it does not come under DCGI purview.
MCI Code of Ethics Regulations recommends the following:
7.22 Research: Clinical drug trials or other research involving patients or volunteers as per the guidelines of ICMR can be undertaken, provided ethical considerations are borne in mind. Violation of existing ICMR guidelines in this regard shall constitute misconduct. Consent taken from the patient for trial of drug or therapy which is not as per the guidelines shall also be construed as misconduct.
Hence the neurosurgeon should follow the ICMR guidelines. These guidelines in ethics committee section cover all types of research and classify it according to the level of risk. The decision re: level of risk is to be made by the EC and not the investigator. Pl also see section on international collaboration and epidemiology. All these point to the need for 1) EC review 2) Informed consent.
CTRI Registration
All interventional clinical trials conducted in India and involving Indian participants need to be registered. An interventional clinical trial is any research study that prospectively assigns people to one or more health-related interventions (e.g., preventive care, drugs, surgical procedures, behavioural treatments, etc.) to evaluate their effects on health-related outcomes. Thus, early and late trials, trials of marketed or non-marketed products, randomized or non-randomized trials - all should be registered.
At present, The CTRI registration is purely voluntary; however, registration is likely to have a lot of advantages both for the registrant as well as the public. Further, prior registration is now a condition of publishing clinical trial data. From 1st July 2005 the International Committee of Medical Journal Editors (ICMJE) have declared that their journals will not publish the results of any clinical trials not included on an authorized register at the trials inception.
Data transfer
As regards data from Indian patients going out, one needs to consider the contribution of this data and the objective of international study. If the study has a large contribution from India, there should be a legal contract with the sponsoring agency re: use of data and potential benefits - authorship, royalty etc.
Subject protection
Providing protection to a subject in case of an injury is responsibility of the investigator and the institute. See ICMR guidelines below:
ICMR guidelines section Compensation For Accidental Injury:
Research participants who suffer physical injury as a result of their participation are entitled to financial or other assistance to compensate them equitably for any temporary or permanent impairment or disability. In case of death, their dependents are entitled to material compensation.
Obligation of the sponsor to pay: The sponsor whether a pharmaceutical company, a government, or an institution, should agree, before the research begins, in the a priori agreement to provide compensation for any physical or psychological injury for which participants are entitled or agree to provide insurance coverage for an unforeseen injury whenever possible
Can a homoeopathic doctor, with 5 years of industry experience as a senior CRA, become sub-investigator?
Dr R Yadav
As per Indian GCP Sub-investigator and Co-investigator are synonymous.
Co-investigator: A person legally qualified to be an investigator, to whom the Investigator delegates a part of his responsibilities.
ICH GCP 1.56 Sub-investigator: Any individual member of the clinical trial team designated and supervised by the investigator at a trial site to perform critical trial-related procedures and/or to make important trial-related decisions (e.g., associates, residents, research fellows).
According to a recent US FDA guidance, during a subject's participation in a trial, the investigator (or designated sub-investigator) should ensure that reasonable medical care is provided to a subject for any adverse events, including clinically significant laboratory values, related to the trial participation.
Considering the above, a sub-investigator has to perform critical trial related procedures, make important decisions, and should be able to provide medical care for adverse events. Hence, the sub-investigator should be legally qualified to undertake these responsibilities.
Hence, a homeopathic doctor would not be able to take the role of a sub-investigator.
How does one report a pregnancy occurring during a trial? As an SAE?
Rohit Shetty
In most international trials, a pregnancy occurring during a trial is reported on a 'pregnancy report form'. In India, there is no regulatory guidance on pregnancy reporting. Hence, it needs to be reported as a serious adverse event.
A pregnancy would be reported as an SAE when there's any complication e.g. miscarriage etc, which meets one of the criteria of seriousness or if the baby is born with congenital defects. However, if a protocol defines all pregnancies to be reported as SAE, one has to follow the protocol.
EC approval is mandatory for all trials including herbal medicines
Wednesday, February 03, 2010 08:00 IST
Dr Arun Bhatt
Medical and scientific judgement should be exercised in deciding whether expedited reporting is appropriate in other situations, such as important medical events that may
What is a bridging study? Do we require DCGI approval for such a study?
V. Sridhar
There is no concept of bridging study in Indian regulations. All Indian trials require DCGI approval
As per ICH E 5
A bridging study is defined as a study performed in the new region to provide pharmacodynamic or clinical data on efficacy, safety, dosage and dose regimen in the new region that will allow extrapolation of the foreign clinical data to the population in the new region.
One of the criteria for the adverse event to be considered as SAE is hospitalization as per the guidelines. But if during the study, the subject is taken to hospital for some time in emergency unit assistance, expert consultation or short-term observation for management of an AE and the subject is discharged on the same day. In that case should we consider it as SAE or not?
Dr Muneesh Garg
US FDA in response a query has advised the following:
“Common usage of "inpatient hospitalization" generally would include being treated by a physician in a hospital for at least a 24-hour period.”
What is the importance of ‘note-to-file' and when it should be a document?
Dr Prakash Atlam
Please see some of the literature excerpts on 'note-to-file'. A Note-to-file is a way to explain any discrepancy in the conduct of a research study or to clarify a decision made in regards to some aspect of the study.
Note-to-file is helpful if it covers the following:
● Identification of a problem
● Identification of a procedural change for preventing recurrence
● Institution of the procedure
Note-to-file is written by site team in site files and in the company files by concerned CRA. It is not submitted to regulatory authorities. However, they can view it in the files.
If there is a regulatory inspection, the inspector may cite the initial problem. However, a note-to-file describing the change in procedure mitigates the citation and supports the site in responding to the finding. .
It is recommended that a 'note-to-file' does not become a device to allow a research investigator or coordinator to ignore protocol or to accept laxity in conduct of a study.
In a clinical trial, is it mandatory that laboratory investigation reports should be signed by MD (Path)?
Shruti Kulkarni
As per NABL, the qualifications required for authorization depends on the nature of lab test. The person could be MD/Phd/MSc/MBBS.
We have got BE NOC (Export) from DCGI - 60 human volunteers and the innovator product is from USA. If we want to conduct the same study with lesser number of volunteers (i.e. <60, say 24) and the innovator product from Europe (same innovator - mfg location is different), whether we need to obtain amendment approval for the approved NOC or to apply fresh NOC or to send an intimation to DCGI without waiting for the approval. Will this change be considered as major or minor?
Balaji K
For the change in number of volunteers, there is no need for amendment, as there is no addition in the number of volunteers.
For the change in manufacturing site, you will require amendment of the import license. If this information is part of protocol, this will be a logistic change which does not require notification / approval of the protocol amendment.
Good Clinical Practices
DCGI permission insists that the sponsor should follow Indian GCP guidelines whilst conducting trial in India
Thursday, April 01, 2010 08:00 IST
Dr Arun Bhatt
If there is no difference between these following two guidelines then why are these prepared separately?
Vij Chauhan
Indian GCP guidelines have been evolved with consideration of WHO, ICH, US FDA and European GCP guidelines as well as the ethical guidelines for biomedical research on human subjects issued by the Indian Council of Medical Research. ICH GCP guideline was developed with consideration of the current good clinical practices of the European Union, Japan, and the United States, as well as those of Australia, Canada, the Nordic countries and the WHO. Due to this, there are differences between ICH and Indian GCP in glossary, ethics segment, safety reporting, monitor’s responsibilities etc. Also, Indian GCP covers areas not covered by ICH GCP e.g. herbal preparations, vaccines, devices etc. Hence, both guidelines need to be followed if an international trial is being conducted in India. DCGI permission insists that the sponsor should follow Indian GCP guidelines whilst conducting the trial in India.
For phase 4 study initiated by pharma co is it necessary to provide study subjects insurance? Is it mandatory to take EC approval from all study centres for phase 4 study initiated by co (non-comparative open label study)? Is it mandatory to take DCGI approval before initiation of phase 4 study?
Dr Arindam Dey
Phase IV can cover different types of studies. (see ICMR 2006 guideline) You need to assess in which category your study falls. If it is an open label study, it will be like a phase III study. Hence, EC approval and patient insurance will be essential. If the indication is not as per DCGI approved indication, it will be necessary to take DCGI approval.
ICMR 2006 guidelines on 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 longterm 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 bioavailabilty 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 labeled 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.
A homoeopathy doc holds a patent for homoeopathic medicine. He wants to run trial with same medicine at his own hospital as principal investigator and will be a self funded trial. No other centre will be involved in trial beside his own hospital. Central lab will be used for blood sample analysis; and an independent monitor will be monitoring this trial. I have following questions: Will it be OK that patent holder investigator can do the trial? Will there be any chance of bias in conduct of trial? How to prevent bias in such trials? Will data generated by this trial be accepted by GCP? Do we require DCGI approval for homoeopathy medicine?
Geeta Talele
A patent holder can conduct the trial. However, his own interest in the product can bias him to give positive results. Hence, he should organize the trial in way that his own interest in the product does not influence the documentation and measurement of efficacy / safety end points. The only way to avoid bias is by letting another investigator conduct the trial. The data will be acceptable if the trial conforms to GCP guidelines. This means that all aspects of the trials - design, conduct, monitoring, recording, analysis, reporting - meet GCP standards, As homoeopathy research comes under Dept of Ayush. You will need to check with them re: Ayush procedures for approval. DCGI approval is not required.
Can we conduct a bioavailability study (pharmacokinetics) for the drug which is not available/approved in India in healthy volunteers (10-12). The objective of the study would be just to understand or analyze the pharmacokinetic behaviour in human subjects. In such scenario only ethics committee approval is sufficient or DCGI approval is required?
Rudolph Almeida
If it is not available/approved in India, you will need a test import license from DCGI office to import the drug for pharmacokinetic study. Hence, DCGI approval of the protocol will be necessary.
ICH GCP requires EC members to be independent of investigator and sponsor to avoid conflicts of interest
Thursday, June 03, 2010 08:00 IST
Dr Arun Bhatt
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.
In India, there is no separate guidance on pregnancy reporting
Thursday, August 05, 2010 08:00 IST
Dr Arun Bhatt
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.u
Clinical trial processes for medical devices are similar to that of drugs
Wednesday, September 01, 2010 08:00 IST
Can you advice how clinical trials can be done using indigenous medical devices in India?
J. Vijayakumar
As of today, most medical devices (a comprehensive & updated list available from the CDSCO website) are considered as drugs for the purpose of clinical trial and come under the purview of the D&C Act. The clinical trial/evaluation process for these devices are similar to that of clinical trial process for drugs in India.
Recently, CDSCO has also released a draft guideline for comments:
● Requirements for conducting clinical trial(s) of medical devices in India
● Guidance document on common submission format for registration of medical devices in India
These guidelines suggest the approach for application/permission for clinical trials. The overall approach is similar to drug trials with specific differences as per nature/type/class of device.
Another draft guideline, the Schedule MIII is available from CDSCO website which outlines the clinical trial process and requirements for devices. Some specific points are as follow; however, this guideline is only a draft and is awaiting finalization.
● Trial should aim at verifying whether the device conforms to 'essential requirements' for medical devices as stipulated in the guideline
● Trial should be compliant to ISO 14155 standard, in addition to Declaration of Helsinki
What are the concerns if we want to set up a Central EC within same group of hosps? What are the issues with having 2 ECs - Central and Local at individual hospitals?
Dr. Sanjay Basumatary
Although the idea looks sound in principle, some concerns remain. These are:
Overall time frame for approval from 2 ECs.
If there is a dispute, whose decision will be final.
Additional burden of the investigator in complying to the documentation/queries of 2 committees
Central EC oversight at trials at different hospitals
Impact duplication of reporting progress report/SAE etc
Perception of sponsors re: above issues and impact on selection of the hospital as a site.
Is there any special requirement for sending the literature cases (articles to accompany the case report) to the DCGI? Moreover, is there any requirement laid down by the Indian regulations to periodically search the relevant literature databases (i.e. Medline) for drugs marketed in India?
Niharika Mathur
There is no specific guidance on this issue. However, the Schedule Y PSUR guidance covers "all the relevant new information from appropriate sources". Hence, it would be important to report literature cases as part of PSUR. See Schedule Y section below: Post Marketing Surveillance - Subsequent to approval of the product, new drugs should be closely monitored for their clinical safety once they are marketed. The applicants shall furnish Periodic Safety Update Reports (PSURs) in order to report all the relevant new information from appropriate sources.
How should the consumer reports be treated for reporting purposes?
Niharika Mathur
If these are safety reports, depending on seriousness, they would be reported either as post-marketing spontaneous reports or as part of PSUR.
For clinical trial events, is any cross reporting required by DCGI for the cases occurring in the same clinical trial in the other centres of the trial (outside India)?
Niharika Mathur
There is no clarity on this issue. Schedule Y and Indian GCP use the words "any" or "all". Hence, most sponsors/CROs report all SAE/ SUSARs from India and other countries to DCGI and participating sites ECS. See Schedule Y section below:
(iv) Any unexpected serious adverse event (SAE) (as defined in GCP guidelines) occurring during a clinical trial should be communicated promptly (within 14 calendar days) by the sponsor to the licensing authority and to the other investigator(s) participating in the study (see Appendix XI).
Indian GCP 3.1.11. Adverse Drug Reaction Reporting:
The sponsor should provide ADR / AE reporting forms to the investigator(s) / institution(s). The sponsor should expedite the reporting to all concerned (including the EC and the regulatory authorities) of all serious and/or unexpected adverse drug reactions.
Also, I have heard that the only way to report to the DCGI is to visit their office in person and get the case report (clinical/post marketing) stamped for acknowledgement? Does the same hold true for PSUR/ annual reports too?
All safety information - SAE / PSUR, has to be submitted in hard copy form personally. This will facilitate getting the acknowledgement on the safety information. There is new annexure form for all notifications to DCGI
Sunday, September 19, 2010
Requirements For Filing Applications for Global Clinical Trial (for submission of data to countries other than India also)
The comments received from various firms and associations were examined and the following requirements were finalized for submission of applications for Global Clinical Trials. The applicants are advised to make applications as per the requirements adherent to the serial numbers given below.
As agreed earlier at the meeting at IDMA office on 17thOctober, 2006 in Mumbai, applications would be scrutinized as mentioned above from 1st December, 2006. The applications, if non-compliant with the requirements mentioned below, shall be rejected.
Requirements For Filing Applications for Global Clinical Trial
(for submission of data to countries other than India also)
1. Name of the Applicant
2. Authorization letter from the Sponsor
3. Name of the Drug
4. Regulatory status of the drug in other countries (Names of countries where the drug is approved along with international package insert or where IND application is filed)
5. Objective of the Study
6. Phase of Study
7. Names of theParticipating Countries /Investigator sites
8. Total no. of patients to be enrolled globally
9. No. of investigator sites to be enrolled in India
10. No. of patients to be included in India
11. Regulatory/ IRB approvals from participating countries
(these approvals should be submitted along with their English translation and reason in case the company is submitting an expired IRB/ IEC approval)
12. Status of the study in other countries
(this should include no. of patients enrolled, no. patients completed the study and no. of patients discontinued)
13. Suspected Unexpected Serious Adverse Reaction (SUSAR) from other participating countries if any reported
14. Affidavit from the sponsor that the study has not been discontinued in any country and in case of discontinuation the reasons for such a discontinuation and that the applicant would further communicate to DCG (I) about future discontinuation
15. Data Submitted
a) Chemical and Pharmaceutical data
i) Generic name and chemical name
ii) Dosage form
iii)Composition
b) Animal Pharmacology Data
c) Animal Toxicology data
d) Clinical data
i) Phase I
ii) Phase II
iii) Phase III
iv) Phase IV
e) Rationale for selecting the proposed dose(s) and indication(s)
15. Documents Submitted
a) Form 44 and Treasury chalan
b) Form 12 and Treasury chalan
c) Details of Biological specimens to be exported
d) Protocol
e) Informed Consent Documents (ICD)
e) Case Report form
f) Investigator’s Brochure duly supported by an affidavit that the summarized information submitted is based on facts
g) Undertakings by the Investigators
h) Ethics committee approvals (if already available)
PROTOCOL AMENDMENTS
a. Those amendments which do not require notification to or permission of the Licensing Authority
i) Administrative and Logistic changes
ii) Minor protocol amendments and additional safety assessments in case the institutional ethics committee has already approved these changes
b. Those amendments which require notification to the Licensing Authority
but need not wait for permission
i) Additional Investigator sites
ii) Change in investigator with the consent to withdraw from the earlier investigator
iii) Amended Investigators Brochure, amended informed consent
c. Those amendments which require prior permission of the Licensing Authority
i) Additional Patients to be recruited
ii) Major changes in protocol with respect to study design, dose and treatment options
iii) Any change in inclusion or exclusion criteria
Note: All amendments must be approved by the concerned Institutional Ethics Committee before their implementation
As agreed earlier at the meeting at IDMA office on 17thOctober, 2006 in Mumbai, applications would be scrutinized as mentioned above from 1st December, 2006. The applications, if non-compliant with the requirements mentioned below, shall be rejected.
Requirements For Filing Applications for Global Clinical Trial
(for submission of data to countries other than India also)
1. Name of the Applicant
2. Authorization letter from the Sponsor
3. Name of the Drug
4. Regulatory status of the drug in other countries (Names of countries where the drug is approved along with international package insert or where IND application is filed)
5. Objective of the Study
6. Phase of Study
7. Names of theParticipating Countries /Investigator sites
8. Total no. of patients to be enrolled globally
9. No. of investigator sites to be enrolled in India
10. No. of patients to be included in India
11. Regulatory/ IRB approvals from participating countries
(these approvals should be submitted along with their English translation and reason in case the company is submitting an expired IRB/ IEC approval)
12. Status of the study in other countries
(this should include no. of patients enrolled, no. patients completed the study and no. of patients discontinued)
13. Suspected Unexpected Serious Adverse Reaction (SUSAR) from other participating countries if any reported
14. Affidavit from the sponsor that the study has not been discontinued in any country and in case of discontinuation the reasons for such a discontinuation and that the applicant would further communicate to DCG (I) about future discontinuation
15. Data Submitted
a) Chemical and Pharmaceutical data
i) Generic name and chemical name
ii) Dosage form
iii)Composition
b) Animal Pharmacology Data
c) Animal Toxicology data
d) Clinical data
i) Phase I
ii) Phase II
iii) Phase III
iv) Phase IV
e) Rationale for selecting the proposed dose(s) and indication(s)
15. Documents Submitted
a) Form 44 and Treasury chalan
b) Form 12 and Treasury chalan
c) Details of Biological specimens to be exported
d) Protocol
e) Informed Consent Documents (ICD)
e) Case Report form
f) Investigator’s Brochure duly supported by an affidavit that the summarized information submitted is based on facts
g) Undertakings by the Investigators
h) Ethics committee approvals (if already available)
PROTOCOL AMENDMENTS
a. Those amendments which do not require notification to or permission of the Licensing Authority
i) Administrative and Logistic changes
ii) Minor protocol amendments and additional safety assessments in case the institutional ethics committee has already approved these changes
b. Those amendments which require notification to the Licensing Authority
but need not wait for permission
i) Additional Investigator sites
ii) Change in investigator with the consent to withdraw from the earlier investigator
iii) Amended Investigators Brochure, amended informed consent
c. Those amendments which require prior permission of the Licensing Authority
i) Additional Patients to be recruited
ii) Major changes in protocol with respect to study design, dose and treatment options
iii) Any change in inclusion or exclusion criteria
Note: All amendments must be approved by the concerned Institutional Ethics Committee before their implementation
Saturday, September 18, 2010
why Appendix XI submitted along with CIOMS to EC
Appendix XI
According to Schedule y the safety reports should be sent to regulatory authorities with in 15 days.Incase if the event experienced by the indian population Appendix XI should be submitted along with CIOMS form.
Data Elements for reporting serious adverse events occuring in a clinical trial
1. Patient Details
Initials & other relevant identifier (hospital/OPD record number etc.)*
Gender
Age and/or date of birth
Weight
Height
2. Suspected Drug(s)
Generic name of the drug*
Indication(s) for which suspect drug was prescribed or tested
Dosage form and strength
Daily dose and regimen (specify units - e.g., mg, ml, mg/kg)
Route of administration
Starting date and time of day
Stopping date and time, or duration of treatment
3. Other Treatment(s)
Provide the same information for concomitant drugs (including non prescription/OTC drugs) and non-drug therapies, as for the suspected drug(s).
4. Details of Suspected Adverse Drug Reaction(s)
Full description of reaction(s) including body site and severity, as well as the criterion (or criteria) for regarding the report as serious. In addition to a description of the reported signs and symptoms, whenever possible, describe a specific diagnosis for the reaction.*
Start date (and time) of onset of reaction
Stop date (and time) or duration of reaction
Dechallenge and rechallenge information
Setting (e.g., hospital, out-patient clinic, home, nursing home)
5. Outcome
Information on recovery and any sequelae; results of specific tests and/or treatment that may have been conducted
For a fatal outcome, cause of death and a comment on its possible relationship to the suspected reaction; Any post-mortem findings.
Other information: anything relevant to facilitate assessment of the case, such as medical history including allergy, drug or alcohol abuse; family history; findings from special investigations etc.
6. Details about the Investigator*
Name
Address
Telephone number
Profession (specialty)
Date of reporting the event to Licensing Authority:
Date of reporting the event to Ethics Committee overseeing the site:
Signature of the Investigator
Note: Information marked * must be provided.”
According to Schedule y the safety reports should be sent to regulatory authorities with in 15 days.Incase if the event experienced by the indian population Appendix XI should be submitted along with CIOMS form.
Data Elements for reporting serious adverse events occuring in a clinical trial
1. Patient Details
Initials & other relevant identifier (hospital/OPD record number etc.)*
Gender
Age and/or date of birth
Weight
Height
2. Suspected Drug(s)
Generic name of the drug*
Indication(s) for which suspect drug was prescribed or tested
Dosage form and strength
Daily dose and regimen (specify units - e.g., mg, ml, mg/kg)
Route of administration
Starting date and time of day
Stopping date and time, or duration of treatment
3. Other Treatment(s)
Provide the same information for concomitant drugs (including non prescription/OTC drugs) and non-drug therapies, as for the suspected drug(s).
4. Details of Suspected Adverse Drug Reaction(s)
Full description of reaction(s) including body site and severity, as well as the criterion (or criteria) for regarding the report as serious. In addition to a description of the reported signs and symptoms, whenever possible, describe a specific diagnosis for the reaction.*
Start date (and time) of onset of reaction
Stop date (and time) or duration of reaction
Dechallenge and rechallenge information
Setting (e.g., hospital, out-patient clinic, home, nursing home)
5. Outcome
Information on recovery and any sequelae; results of specific tests and/or treatment that may have been conducted
For a fatal outcome, cause of death and a comment on its possible relationship to the suspected reaction; Any post-mortem findings.
Other information: anything relevant to facilitate assessment of the case, such as medical history including allergy, drug or alcohol abuse; family history; findings from special investigations etc.
6. Details about the Investigator*
Name
Address
Telephone number
Profession (specialty)
Date of reporting the event to Licensing Authority:
Date of reporting the event to Ethics Committee overseeing the site:
Signature of the Investigator
Note: Information marked * must be provided.”
Sunday, August 22, 2010
Wednesday, April 14, 2010
Wednesday, January 13, 2010
Tuesday, January 12, 2010
Monday, January 11, 2010
regulations apply to the IND application process
The following regulations apply to the IND application process:
21CFR Part 312 Investigational New Drug Application
21CFR Part 314 INDA and NDA Applications for FDA Approval to Market a New Drug (New Drug Approval)
21CFR Part 316 Orphan Drugs
21CFR Part 58 Good Lab Practice for Nonclinical Laboratory [Animal] Studies
21CFR Part 50 Protection of Human Subjects
21CFR Part 56 Institutional Review Boards
21CFR Part 201 Drug Labeling
21CFR Part 54 Financial Disclosure by Clinical Investigators
21CFR Part 312 Investigational New Drug Application
21CFR Part 314 INDA and NDA Applications for FDA Approval to Market a New Drug (New Drug Approval)
21CFR Part 316 Orphan Drugs
21CFR Part 58 Good Lab Practice for Nonclinical Laboratory [Animal] Studies
21CFR Part 50 Protection of Human Subjects
21CFR Part 56 Institutional Review Boards
21CFR Part 201 Drug Labeling
21CFR Part 54 Financial Disclosure by Clinical Investigators
Sunday, January 10, 2010
Phases
Phase No. patients Duration Location Purpose
I 20–80
(healthy) 36 hours, over 2–6 weekends Single site Bioavailability, pharmacokinetics, safety, dosing regimens/ranges
II 50–200
(diseased) 36 hours, over 1–4 weekends Single site Safety and preliminary efficacy
III 100–2000
(diseased) 6 months–
3 years 30–40 sites Immediate and long-term safety and efficacy
IVa 100–2000
(diseased) 6 months–
3 years 30–40 sites Efficacy for alternate indications
sample protocol
see also in www.med.upenn.edu/ohr/protocol/sample/sample.html
GUIDE TO CLINICAL TRIAL PROTOCOL
CONTENT AND FORMAT
The aim of this guide is to help researchers with the content and structure of protocols for clinical trials. It indicates the information that should generally be included in a protocol and has been constructed to cover important methodological considerations and requirements specified under Good Clinical Practice. This guide refers primarily to trials of medicinal products, however many aspects will also be relevant to other types of intervention. There are links in this document to obtain more information about some topics, and a list of recommended references at the end.
Please note that if you are submitting your trial to the MHRA for a Clinical Trials
Authorisation then other information will also be required. The UCL Clinical Research Network have written a guidance document which can be obtained from
jessica.crellin@royalfree.nhs.uk. Detailed information can also be obtained from the MHRA website.Many of the methodological aspects of designing a research study and writing a protocol can benefit from the advice of a statistician. Such advice should be sought at an early stage and is available for UCLH researchers through the R&D Medical Statistics Unit.
1. TITLE PAGE
1.1 Title
It is useful to specify both a full title and short title
• The full title should include summary study design, medicinal product(s), nature of the treatment, comparators and/or any placebo, indication, patient population and setting.
• The short title is a summary of this The titles specified must be consistent across all documents relevant to the trial
1.2 Names (titles), roles and contact details of:
• Authors, investigators, experts and advisors involved in the trial
• Sponsor & monitor – as agreed with Chief / principal investigator’s employer and the host Trust
• Trial site(s), clinical laboratory(s), technical departments and institutions involved in the study
1.3 Protocol details
• Version number
• final / draft
• Date
2. SIGNATURE PAGE
Signatures of all healthcare professionals involved in the trial
3. CONTENTS PAGE
4. LIST OF ABBREVIATIONS AND DEFINITIONS
5. SUMMARY
1 or 2 page summary including:
• Aim and rationale for the trial
• Summary of trial disorder / interventions / measures
• Primary & secondary objectives
• Brief description of methods
6. BACKGROUND
The detail given in this section should be backed up by a full literature review and should make reference to relevant papers, previous clinical experience and pilot work.
This section should include:
• A clear explanation of the main research question i.e. the hypothesis to be tested
• Detailed justification for the trial including :
- explanation of why the study is appropriate, potential benefits to patients/ health service, relevance to current policies and priorities.
- description of the indication, its diagnosis, incidence, current treatments and their limitations
- description of the treatment under investigation including reference to any previous evidence of its usefulness
- a statement of what would be a worthwhile improvement in study outcomes and
what evidence there is that the treatment under investigation may achieve this.
7. TRIAL OBJECTIVES AND PURPOSE
• Purpose of research (e.g student project, commercial / non commercial trial, licensing)
• clearly define and distinguish primary and secondary objectives (including examination
of effects for defined subgroups of patients)
8. STUDY DESIGN
• statement of the primary and secondary endpoints / outcomes (including at what point in
the trial these will be measured)
• clear description and justification of the type of design (e.g parallel group / crossover, sequential, cluster randomised and equivalence)
- if crossover design, include information about possible carry over effects, detail of orderings, washout (/in) periods etc
• Phase of the trial (e.g. phase I / II / III / pilot study)
• summary of treatments being compared with reasons for choice of comparison group
(e.g active control / placebo)
• schematic diagram(s) of the trial design, procedures, stages and data collection
• description and justification of the duration of treatment, subject participation and trial follow-up
9. SUBJECT SELECTION
Include detail of:
• Source of subjects (where they come from and why this group is appropriate)
• Number of centres involved
• Subject inclusion and exclusion criteria (with justification if necessary – for example consider contra-indications to trial treatments, incompatible concurrent treatments, recent involvement in other research)
• Expected no of eligible participants available per year and proportion of these expected to agree to the trial
210. SUBJECT RECRUITMENT
Details of recruitment process including
• method of recruitment (eg via adverts, clinics)
• payment of participants
• details of procedures, tests, screenings carried out to assess trial suitability
• Provision of patient information sheet (include as appendix)
• gaining patient consent (how consent will be obtained, who will gain consent,
whether a witness will be present, how long the subject will have to decide, the
arrangements for non English speakers and special groups (e.g. mentally ill,
children, those suffering from dementia.)
• detail of enrolment procedure
11. TRIAL INTERVENTIONS
This refers to the treatment under investigation and any active control treatment. Detail in this section may be referenced to other documents, such as the Investigators Brochure.
11.1 General information
• full name, generic name (if appropriate) and if licensed in UK trade name.
• licence information - UK or EU (as appropriate)
• The Summary of Product Characteristics or the Data Sheet for Licensed Medicinal
Products.
• summary of known and potential risks and benefits to human subjects
11.2 Use within the trial
• description and justification for the proposed route of administration, dosage, and treatment period
• detail of who will be administering the product ( eg patient, nurse, doctor, carer)
• is the treatment invasive / does it involve radioactive substances?
• description of dosage form, packaging and labelling of products
• description of dispensing records, accountability and disposal procedures during the trial
• details of who will supply the products
• other detail including shelf life, arrangements for storage etc
• arrangements for continuation of treatment for study patients after the end of the trial
• Other medications permitted during the trial - include rescue medication (could be
standardised for the purposes of the trial). Important also to consider possible
interactions or effects that could confound results / conclusions
12. RANDOMISATION
Including detail and justification for each of the following :
• patient / cluster randomised design (randomising individuals or groups (e.g. general practices, wards)
• type of randomisation to be used - simple, block, stratified, minimisation
- if stratified include definition of stratification variables
- if blocked define block sizes and whether these will vary.
• use of equal or unequal allocation between treatment arms
• information regarding how randomisation will be implemented (including who, where,
how)
• approach to be used to conceal allocation (e.g. sealed envelopes, telephone central allocation office, computerised randomisation etc)
313. BLINDING & OTHER MEASURES TAKEN TO AVOID BIAS
13.1 Blinding
Detail and justification for:
• measurements to be blinded
• level of blinding to be used – e.g. blinding of participants / investigators / assessors (i.e. double blind, single blind, open)
• how blinding will be implemented (e.g. through use of identical placebo)
13.2 Other measures taken to minimise / avoid bias
14. DATA
14.1 Data to be collected
• provide a detailed list of all data (outcome variables, explanatory variables etc) to be
collected, with each description including :
- source of the data (e.g. patient questionnaires, patient notes, electronic data, procedure)
- time point for collection (baseline, during treatment, at followup point)
- who will collect the data
- why the data is being collected (e.g. baseline comparison data, main outcome,
important prognostic / explanatory variable)
- whether the data is from a standardised tool (e.g. McGill pain score) / involves a
procedure (in which case full details should be supplied). If a non standard tool is to be used, detail on reliability and validity should be given.
- what form the data will take (e.g binary, continuous (numeric), time to event)
• useful to include table / diagram describing schedule for data collection.
• describe methods used to maximise completeness of data (e.g. telephoning patients who have not returned postal questionnaires)
• include data collection forms as appendices
14.2 Data handling and record keeping
• describe procedures for data collection and recording (software to be used, location of the data etc)
• detail methods implemented to ensure validity and quality of data (e.g double entry, cross validation etc)
• Security / storage of data
• Records retention – duration and location
• Adherence to Data Protection Act 1998
• statement of who is responsible for data collection, recording and quality
15 STATISTICAL CONSIDERATIONS
15.1 Statistical analysis
• Detail of the variables to be used to assess baseline comparability of the randomised groups and how these will be reported (e.g. means, standard deviations, medians, proportions)
• Detailed plans for statistical analyses of primary and secondary outcomes including:
- summary measures to be reported
- method of analysis (justified with consideration of assumptions of the method,
structure of the data (e.g. unpaired, paired, hierarchical) etc)
- plans for handling missing data, non compliers and withdrawals in analysis
- plans for predefined subgroup analyses
4- Statement regarding use of intention to treat (ITT) analysis
• Detail of approach for interim analyses and criteria for early termination of the trial
• Detail of any non statistical methods that might be used (e.g qualitative methods)
• Statement of who will carry out analyses and at what point
15.2 Sample size calculation
• Details of the precision or power calculation used to estimate the required sample size (for analysis of the primary outcome), including :
- estimates used (e.g. size of the clinically important effect to be detected, drop out / non compliance rates)
- assumptions made (e.g. assumptions of Normality)
- relevant justification (i.e. appropriate references or clinical arguments)
- allowance for planned subgroup analyses
- chosen levels of significance and power
- methods / formula / software used
• An estimate of the recruitment period for the trial (calculated based on the expected
number of eligible and recruited participants available per year) with justification that the required sample size will be attainable in practice.
16. COMPLIANCE AND WITHDRAWAL
16.1 Subject compliance
• procedures for monitoring (e.g. watching subject swallow pills and checking their
mouths afterwards)
• recording of patient compliance information (what will be recorded, when and where)
• detail of follow-up of non compliant subjects
16.2 Withdrawal / dropout of subjects
• describe under what circumstances and how subjects will be withdrawn from the trial
• give details of documentation to be completed on subject withdrawal (including
recording reasons for withdrawal and any follow-up information collected)
• whether and how subjects would be replaced
17. INTERIM ANALYSIS AND DATA MONITORING
17.1 Stopping / discontinuation rules and breaking of randomisation code
• define completion and premature discontinuation of the trial
• describe procedure regarding decisions on discontinuation of the trial (e.g interim analyses, role of data monitoring committee)
• state documentation to be completed if part / all of the trial is discontinued
• describe circumstances under which the randomisation codes may need to be broken and the procedure for this.
17.2 Monitoring, quality control and assurance
• use and role of monitors eg data monitoring groups and steering groups and
arrangements for monitoring / auditing conduct of the research
• Assurance on good clinical practice and adherence to research governance guidelines
• Detail of any other steps taken to ensure quality of research
517.3 Assessment of safety or pharmocovigilance
NB With the implementation of the Clinical Trial Regulations 2004 there are new
requirements around the reporting of adverse events. The final guidance has not yet
been issued and further links to relevant policies will be made when these become
available.
• Definition of serious adverse events for the trial which are expected e.g. hospitalisation
in terminally ill patients.
• Statements about which serious expected adverse events will not be reported.
• A statement about how non serious adverse events will be recorded and reported.
• Details of the procedures that will be followed in the event of adverse events in the trial
– who has what responsibility
• methods and timing for assessing, recording and analysing safety parameters (e.g
interim analyses)
• The type and duration of follow up for subjects after adverse events
18 ETHICAL CONSIDERATIONS
Description of ethical issues for the trial. For example consider:
• Approvals from relevant groups (e.g. MREC, LREC, MHRA, Trust(s))
• Informed consent (append information sheet and informed consent form)
• Allowances for special groups (e.g non English speakers, children, mentally ill)
• Patient withdrawal / discontinuation
• Trial monitoring
19 FINANCING AND INSURANCE
• Finance and insurance details (if not addressed in separate agreement)
• Cover for non negligent and negligent harm
20 REPORTING AND DISSEMINATION
Detail of publication policy (e.g. Following the study, will there be access to raw data and
right to publication freely by all investigators in the study?, what publications / conference
presentations will be planned)
TABLES, FIGURES, REFERENCES
APPENDICES
Including (where relevant):
• Patient information sheet
• Patient consent form
• Data collection forms and validation information
• Summary of product characteristics
• ethics form
• investigators brochure
6Useful reading
Websites
• Martin Bland et al, Statistics guide for research grant applications
(http://www.sghms.ac.uk/depts/phs/guide/guide.htm#brief)
includes detailed information and definitions of many aspects required for a research
protocol as well as information about randomisation software and services
• Symptoms research : Methods and opportunities. Edited by M. Mitchell & J. Lynn
(http://symptomresearch.nih.gov/preface/index.htm)
This online textbook includes some useful chapters for clinical trials, in particular a chapter on cross over trials by Stephen Senn.
• CONSORT statement (www.consort-statement.org)
A set of recommendations for improving the quality of reports of parallel group
randomised trials
• Declaration of Helsinki (www.wma.net/e/policy/b3.htm)
Provides ethical principles for medical research involving human subjects
• COREC guidelines (www.corec.org.uk)
Includes patient information sheet and consent form guidelines
• ICH Harmonised Tripartite Guidelines for Good Clinical Practice (1996)
(www.emea.eu.int/pdfs/human/ich/01359sen.pdf)
BooksAltman, DG. Practical Statistics for Medical Research. London: Chapman and Hall, 1991, Chapter 15.
Machin D, Campbell MJ, Fayers PM and Pinol APY Sample Size Tables for Clinical Studies. Second Edition. Oxford: Blackwell Science, 1997.
Friedman LM, Furberg CD, DeMets DL. Fundamentals of Clinical Trials. 3rd
edition. New York: Springer; 1998.
Jadad A. Randomised Controlled Trials. London: BMJ Books, 1998.
Pocock S. Clinical trials: a practical approach. Chichester: Wiley, 1983.
Senn S. Cross-over trials in clinical research. Chichester: Wiley, 1993.
Papers
BMJ statistics notes provide some brief but useful information on various topics including :
Bland JM, Kerry SM. Trials randomised in clusters. BMJ 1997; 315:600
Kerry SM, Bland JM. Analysis of a trial randomised in clusters. BMJ 1998; 316:54
Altman DG, Bland JM. Treatment allocation in controlled trials: why randomise. BMJ 1999; 318:1209
Altman DG, Bland JM. How to randomise. BMJ 1999; 319:703-704
7Day JD, Altman DG. Blinding in clinical trials and other studies. BMJ 2000; 321: 504
Altman DG, Schulz KF. Concealing treatment allocation in randomised trials. BMJ 2001;
323:446-447.
Other relevant papers are:
Altman DG. The comparability of randomised groups. Statistician 1985; 34: 125-136.
Altman DG, Doré CJ. Randomisation and baseline comparisons in clinical trials. Lancet 1990; 335:
149-153.
Moher D, Schulz KF, Altman DG for the CONSORT Group. The CONSORT statement: revised
recommendations for improving the quality of reports of parallel-group randomised trials. Lancet
2001;357:1191-1194.
Altman DG, Schulz KF, Moher D, Egger M, Davidoff, Elbourne D, Gøtzsche PC, Lang T for the
CONSORT Group. The revised CONSORT statement for reporting randomized trials: explanation
and elaboration. Annals of Internal Medicine 2001; 134: 663-694.
Campbell MK, Grimshaw JM. Cluster randomised trials: time for improvement. BMJ 1998; 317:
1171-1172.
Scott NW, McPherson GC, Ramsay CR, Campbell MK. The method of minimisation for allocation to
clinical trials: a review. Controlled Clinical Trials 2002; 23: 662-674
Jüni P, Altman DG, Egger M. Assessing the quality of controlled clinical trials. British Medical
Journal 2001; 323: 42-46.
Lachin JM. Statistical considerations in the intent-to-treat principle. Controlled Clinical Trials 2000;
21:167-189.
Pocock S. Current issues in the design and interpretation of clinical trials. BMJ 1985; 290: 39-42.
Schulz KF, Grimes DA. Allocation concealment in randomised trials: defending against deciphering.
Lancet 2002a; 359: 614-618.
Schulz KF, Grimes DA. Blinding in randomised trials: hiding who got what. Lancet 2002b; 359: 696-
700.
Vickers AJ, Altman DG. Analysing controlled trials with baseline and follow-up measurements.
BMJ 2001; 323: 1123-1124.
Gibbons, A. Performing and publishing a randomised controlled trial. BMJ 2002 324, S131.
Medical Statistics Unit, UCLH R & D directorate
January 2006
GUIDE TO CLINICAL TRIAL PROTOCOL
CONTENT AND FORMAT
The aim of this guide is to help researchers with the content and structure of protocols for clinical trials. It indicates the information that should generally be included in a protocol and has been constructed to cover important methodological considerations and requirements specified under Good Clinical Practice. This guide refers primarily to trials of medicinal products, however many aspects will also be relevant to other types of intervention. There are links in this document to obtain more information about some topics, and a list of recommended references at the end.
Please note that if you are submitting your trial to the MHRA for a Clinical Trials
Authorisation then other information will also be required. The UCL Clinical Research Network have written a guidance document which can be obtained from
jessica.crellin@royalfree.nhs.uk. Detailed information can also be obtained from the MHRA website.Many of the methodological aspects of designing a research study and writing a protocol can benefit from the advice of a statistician. Such advice should be sought at an early stage and is available for UCLH researchers through the R&D Medical Statistics Unit.
1. TITLE PAGE
1.1 Title
It is useful to specify both a full title and short title
• The full title should include summary study design, medicinal product(s), nature of the treatment, comparators and/or any placebo, indication, patient population and setting.
• The short title is a summary of this The titles specified must be consistent across all documents relevant to the trial
1.2 Names (titles), roles and contact details of:
• Authors, investigators, experts and advisors involved in the trial
• Sponsor & monitor – as agreed with Chief / principal investigator’s employer and the host Trust
• Trial site(s), clinical laboratory(s), technical departments and institutions involved in the study
1.3 Protocol details
• Version number
• final / draft
• Date
2. SIGNATURE PAGE
Signatures of all healthcare professionals involved in the trial
3. CONTENTS PAGE
4. LIST OF ABBREVIATIONS AND DEFINITIONS
5. SUMMARY
1 or 2 page summary including:
• Aim and rationale for the trial
• Summary of trial disorder / interventions / measures
• Primary & secondary objectives
• Brief description of methods
6. BACKGROUND
The detail given in this section should be backed up by a full literature review and should make reference to relevant papers, previous clinical experience and pilot work.
This section should include:
• A clear explanation of the main research question i.e. the hypothesis to be tested
• Detailed justification for the trial including :
- explanation of why the study is appropriate, potential benefits to patients/ health service, relevance to current policies and priorities.
- description of the indication, its diagnosis, incidence, current treatments and their limitations
- description of the treatment under investigation including reference to any previous evidence of its usefulness
- a statement of what would be a worthwhile improvement in study outcomes and
what evidence there is that the treatment under investigation may achieve this.
7. TRIAL OBJECTIVES AND PURPOSE
• Purpose of research (e.g student project, commercial / non commercial trial, licensing)
• clearly define and distinguish primary and secondary objectives (including examination
of effects for defined subgroups of patients)
8. STUDY DESIGN
• statement of the primary and secondary endpoints / outcomes (including at what point in
the trial these will be measured)
• clear description and justification of the type of design (e.g parallel group / crossover, sequential, cluster randomised and equivalence)
- if crossover design, include information about possible carry over effects, detail of orderings, washout (/in) periods etc
• Phase of the trial (e.g. phase I / II / III / pilot study)
• summary of treatments being compared with reasons for choice of comparison group
(e.g active control / placebo)
• schematic diagram(s) of the trial design, procedures, stages and data collection
• description and justification of the duration of treatment, subject participation and trial follow-up
9. SUBJECT SELECTION
Include detail of:
• Source of subjects (where they come from and why this group is appropriate)
• Number of centres involved
• Subject inclusion and exclusion criteria (with justification if necessary – for example consider contra-indications to trial treatments, incompatible concurrent treatments, recent involvement in other research)
• Expected no of eligible participants available per year and proportion of these expected to agree to the trial
210. SUBJECT RECRUITMENT
Details of recruitment process including
• method of recruitment (eg via adverts, clinics)
• payment of participants
• details of procedures, tests, screenings carried out to assess trial suitability
• Provision of patient information sheet (include as appendix)
• gaining patient consent (how consent will be obtained, who will gain consent,
whether a witness will be present, how long the subject will have to decide, the
arrangements for non English speakers and special groups (e.g. mentally ill,
children, those suffering from dementia.)
• detail of enrolment procedure
11. TRIAL INTERVENTIONS
This refers to the treatment under investigation and any active control treatment. Detail in this section may be referenced to other documents, such as the Investigators Brochure.
11.1 General information
• full name, generic name (if appropriate) and if licensed in UK trade name.
• licence information - UK or EU (as appropriate)
• The Summary of Product Characteristics or the Data Sheet for Licensed Medicinal
Products.
• summary of known and potential risks and benefits to human subjects
11.2 Use within the trial
• description and justification for the proposed route of administration, dosage, and treatment period
• detail of who will be administering the product ( eg patient, nurse, doctor, carer)
• is the treatment invasive / does it involve radioactive substances?
• description of dosage form, packaging and labelling of products
• description of dispensing records, accountability and disposal procedures during the trial
• details of who will supply the products
• other detail including shelf life, arrangements for storage etc
• arrangements for continuation of treatment for study patients after the end of the trial
• Other medications permitted during the trial - include rescue medication (could be
standardised for the purposes of the trial). Important also to consider possible
interactions or effects that could confound results / conclusions
12. RANDOMISATION
Including detail and justification for each of the following :
• patient / cluster randomised design (randomising individuals or groups (e.g. general practices, wards)
• type of randomisation to be used - simple, block, stratified, minimisation
- if stratified include definition of stratification variables
- if blocked define block sizes and whether these will vary.
• use of equal or unequal allocation between treatment arms
• information regarding how randomisation will be implemented (including who, where,
how)
• approach to be used to conceal allocation (e.g. sealed envelopes, telephone central allocation office, computerised randomisation etc)
313. BLINDING & OTHER MEASURES TAKEN TO AVOID BIAS
13.1 Blinding
Detail and justification for:
• measurements to be blinded
• level of blinding to be used – e.g. blinding of participants / investigators / assessors (i.e. double blind, single blind, open)
• how blinding will be implemented (e.g. through use of identical placebo)
13.2 Other measures taken to minimise / avoid bias
14. DATA
14.1 Data to be collected
• provide a detailed list of all data (outcome variables, explanatory variables etc) to be
collected, with each description including :
- source of the data (e.g. patient questionnaires, patient notes, electronic data, procedure)
- time point for collection (baseline, during treatment, at followup point)
- who will collect the data
- why the data is being collected (e.g. baseline comparison data, main outcome,
important prognostic / explanatory variable)
- whether the data is from a standardised tool (e.g. McGill pain score) / involves a
procedure (in which case full details should be supplied). If a non standard tool is to be used, detail on reliability and validity should be given.
- what form the data will take (e.g binary, continuous (numeric), time to event)
• useful to include table / diagram describing schedule for data collection.
• describe methods used to maximise completeness of data (e.g. telephoning patients who have not returned postal questionnaires)
• include data collection forms as appendices
14.2 Data handling and record keeping
• describe procedures for data collection and recording (software to be used, location of the data etc)
• detail methods implemented to ensure validity and quality of data (e.g double entry, cross validation etc)
• Security / storage of data
• Records retention – duration and location
• Adherence to Data Protection Act 1998
• statement of who is responsible for data collection, recording and quality
15 STATISTICAL CONSIDERATIONS
15.1 Statistical analysis
• Detail of the variables to be used to assess baseline comparability of the randomised groups and how these will be reported (e.g. means, standard deviations, medians, proportions)
• Detailed plans for statistical analyses of primary and secondary outcomes including:
- summary measures to be reported
- method of analysis (justified with consideration of assumptions of the method,
structure of the data (e.g. unpaired, paired, hierarchical) etc)
- plans for handling missing data, non compliers and withdrawals in analysis
- plans for predefined subgroup analyses
4- Statement regarding use of intention to treat (ITT) analysis
• Detail of approach for interim analyses and criteria for early termination of the trial
• Detail of any non statistical methods that might be used (e.g qualitative methods)
• Statement of who will carry out analyses and at what point
15.2 Sample size calculation
• Details of the precision or power calculation used to estimate the required sample size (for analysis of the primary outcome), including :
- estimates used (e.g. size of the clinically important effect to be detected, drop out / non compliance rates)
- assumptions made (e.g. assumptions of Normality)
- relevant justification (i.e. appropriate references or clinical arguments)
- allowance for planned subgroup analyses
- chosen levels of significance and power
- methods / formula / software used
• An estimate of the recruitment period for the trial (calculated based on the expected
number of eligible and recruited participants available per year) with justification that the required sample size will be attainable in practice.
16. COMPLIANCE AND WITHDRAWAL
16.1 Subject compliance
• procedures for monitoring (e.g. watching subject swallow pills and checking their
mouths afterwards)
• recording of patient compliance information (what will be recorded, when and where)
• detail of follow-up of non compliant subjects
16.2 Withdrawal / dropout of subjects
• describe under what circumstances and how subjects will be withdrawn from the trial
• give details of documentation to be completed on subject withdrawal (including
recording reasons for withdrawal and any follow-up information collected)
• whether and how subjects would be replaced
17. INTERIM ANALYSIS AND DATA MONITORING
17.1 Stopping / discontinuation rules and breaking of randomisation code
• define completion and premature discontinuation of the trial
• describe procedure regarding decisions on discontinuation of the trial (e.g interim analyses, role of data monitoring committee)
• state documentation to be completed if part / all of the trial is discontinued
• describe circumstances under which the randomisation codes may need to be broken and the procedure for this.
17.2 Monitoring, quality control and assurance
• use and role of monitors eg data monitoring groups and steering groups and
arrangements for monitoring / auditing conduct of the research
• Assurance on good clinical practice and adherence to research governance guidelines
• Detail of any other steps taken to ensure quality of research
517.3 Assessment of safety or pharmocovigilance
NB With the implementation of the Clinical Trial Regulations 2004 there are new
requirements around the reporting of adverse events. The final guidance has not yet
been issued and further links to relevant policies will be made when these become
available.
• Definition of serious adverse events for the trial which are expected e.g. hospitalisation
in terminally ill patients.
• Statements about which serious expected adverse events will not be reported.
• A statement about how non serious adverse events will be recorded and reported.
• Details of the procedures that will be followed in the event of adverse events in the trial
– who has what responsibility
• methods and timing for assessing, recording and analysing safety parameters (e.g
interim analyses)
• The type and duration of follow up for subjects after adverse events
18 ETHICAL CONSIDERATIONS
Description of ethical issues for the trial. For example consider:
• Approvals from relevant groups (e.g. MREC, LREC, MHRA, Trust(s))
• Informed consent (append information sheet and informed consent form)
• Allowances for special groups (e.g non English speakers, children, mentally ill)
• Patient withdrawal / discontinuation
• Trial monitoring
19 FINANCING AND INSURANCE
• Finance and insurance details (if not addressed in separate agreement)
• Cover for non negligent and negligent harm
20 REPORTING AND DISSEMINATION
Detail of publication policy (e.g. Following the study, will there be access to raw data and
right to publication freely by all investigators in the study?, what publications / conference
presentations will be planned)
TABLES, FIGURES, REFERENCES
APPENDICES
Including (where relevant):
• Patient information sheet
• Patient consent form
• Data collection forms and validation information
• Summary of product characteristics
• ethics form
• investigators brochure
6Useful reading
Websites
• Martin Bland et al, Statistics guide for research grant applications
(http://www.sghms.ac.uk/depts/phs/guide/guide.htm#brief)
includes detailed information and definitions of many aspects required for a research
protocol as well as information about randomisation software and services
• Symptoms research : Methods and opportunities. Edited by M. Mitchell & J. Lynn
(http://symptomresearch.nih.gov/preface/index.htm)
This online textbook includes some useful chapters for clinical trials, in particular a chapter on cross over trials by Stephen Senn.
• CONSORT statement (www.consort-statement.org)
A set of recommendations for improving the quality of reports of parallel group
randomised trials
• Declaration of Helsinki (www.wma.net/e/policy/b3.htm)
Provides ethical principles for medical research involving human subjects
• COREC guidelines (www.corec.org.uk)
Includes patient information sheet and consent form guidelines
• ICH Harmonised Tripartite Guidelines for Good Clinical Practice (1996)
(www.emea.eu.int/pdfs/human/ich/01359sen.pdf)
BooksAltman, DG. Practical Statistics for Medical Research. London: Chapman and Hall, 1991, Chapter 15.
Machin D, Campbell MJ, Fayers PM and Pinol APY Sample Size Tables for Clinical Studies. Second Edition. Oxford: Blackwell Science, 1997.
Friedman LM, Furberg CD, DeMets DL. Fundamentals of Clinical Trials. 3rd
edition. New York: Springer; 1998.
Jadad A. Randomised Controlled Trials. London: BMJ Books, 1998.
Pocock S. Clinical trials: a practical approach. Chichester: Wiley, 1983.
Senn S. Cross-over trials in clinical research. Chichester: Wiley, 1993.
Papers
BMJ statistics notes provide some brief but useful information on various topics including :
Bland JM, Kerry SM. Trials randomised in clusters. BMJ 1997; 315:600
Kerry SM, Bland JM. Analysis of a trial randomised in clusters. BMJ 1998; 316:54
Altman DG, Bland JM. Treatment allocation in controlled trials: why randomise. BMJ 1999; 318:1209
Altman DG, Bland JM. How to randomise. BMJ 1999; 319:703-704
7Day JD, Altman DG. Blinding in clinical trials and other studies. BMJ 2000; 321: 504
Altman DG, Schulz KF. Concealing treatment allocation in randomised trials. BMJ 2001;
323:446-447.
Other relevant papers are:
Altman DG. The comparability of randomised groups. Statistician 1985; 34: 125-136.
Altman DG, Doré CJ. Randomisation and baseline comparisons in clinical trials. Lancet 1990; 335:
149-153.
Moher D, Schulz KF, Altman DG for the CONSORT Group. The CONSORT statement: revised
recommendations for improving the quality of reports of parallel-group randomised trials. Lancet
2001;357:1191-1194.
Altman DG, Schulz KF, Moher D, Egger M, Davidoff, Elbourne D, Gøtzsche PC, Lang T for the
CONSORT Group. The revised CONSORT statement for reporting randomized trials: explanation
and elaboration. Annals of Internal Medicine 2001; 134: 663-694.
Campbell MK, Grimshaw JM. Cluster randomised trials: time for improvement. BMJ 1998; 317:
1171-1172.
Scott NW, McPherson GC, Ramsay CR, Campbell MK. The method of minimisation for allocation to
clinical trials: a review. Controlled Clinical Trials 2002; 23: 662-674
Jüni P, Altman DG, Egger M. Assessing the quality of controlled clinical trials. British Medical
Journal 2001; 323: 42-46.
Lachin JM. Statistical considerations in the intent-to-treat principle. Controlled Clinical Trials 2000;
21:167-189.
Pocock S. Current issues in the design and interpretation of clinical trials. BMJ 1985; 290: 39-42.
Schulz KF, Grimes DA. Allocation concealment in randomised trials: defending against deciphering.
Lancet 2002a; 359: 614-618.
Schulz KF, Grimes DA. Blinding in randomised trials: hiding who got what. Lancet 2002b; 359: 696-
700.
Vickers AJ, Altman DG. Analysing controlled trials with baseline and follow-up measurements.
BMJ 2001; 323: 1123-1124.
Gibbons, A. Performing and publishing a randomised controlled trial. BMJ 2002 324, S131.
Medical Statistics Unit, UCLH R & D directorate
January 2006
Sulfonylureas Linked to Higher Risks of Death and Heart Failure
Brain Mind behaviour neuroscices Research institute
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Sulfonylureas Linked to Higher Risks of Death and Heart Failure
Sulfonylurea monotherapy for type 2 diabetes was associated with increased risks of all-cause death and congestive heart failure compared with metformin, a large, retrospective study showed.
Through a mean follow-up of 7.1 years, both first-generation (HR 1.37, 95% CI 1.11 to 1.71) and second-generation (HR 1.24, 95% CI 1.14 to 1.35) sulfonylureas were associated with elevated mortality risks, according to Paul Elliott, MBBS, PhD, of Imperial College London, and colleagues.
Second-generation drugs in that class were associated with an 18% higher risk of developing congestive heart failure (HR 1.18, 95% CI 1.04 to 1.34), they wrote online in BMJ.
The findings are "consistent with the recommendations of the American Diabetes Association and International Diabetes Federation that favor metformin as the initial treatment for type 2 diabetes," the researchers wrote.
Commenting on the study, Vivian Fonseca, MD, of Tulane University in New Orleans, pointed out several limitations inherent to this and other retrospective studies, including selection bias. He wrote in an e-mail that it is impossible to know the reasons individual patients were prescribed certain drugs.
For example, he wrote, high-risk patients with elevated creatinine will not be prescribed metformin, but might possibly receive a sulfonylurea instead. Because the patients are already at high risk, incident cardiovascular events cannot necessarily be blamed on the medication.
Some previous studies have suggested that certain oral diabetes drugs increase the risk of cardiovascular events, whereas others have failed to show a relationship.
To explore the issue, Elliott and his colleagues looked at data from 91,521 men and women with diabetes (mean age 65) from the U.K. General Practice Research Database.
The patients' glycosylated hemoglobin (HbA1c) levels ranged from 8.1% to 8.5%.
Three-quarters (74.5%) were being treated with metformin monotherapy. The next most common regimen (for 63.5%) was monotherapy with second-generation sulfonylureas.
Through a mean follow-up of 7.1 years, there were 3,588 incident myocardial infarctions, 6,900 cases of congestive heart failure, and 18,548 deaths.
The researchers examined the relationship of diabetes treatment with each of these events. Fully adjusted models controlled for sex, duration of diabetes, previous complications from diabetes, previous peripheral artery disease, previous cardiovascular disease, other medications, body mass index, cholesterol levels, systolic blood pressure, HbA1c, creatinine and albumin concentrations, and smoking status.
None of the treatments included in the study had a significant association with risk of MI.
However, compared with metformin monotherapy, second-generation sulfonylurea monotherapy was linked to a greater risk of developing congestive heart failure (P=0.011).
Monotherapy with first- and second-generation sulfonylureas was associated with increased risks of all-cause death during follow-up (P=0.0003 and P<0.001, respectively).
Neither of the thiazolidinediones examined -- pioglitazone (Actos) and rosiglitazone (Avandia) -- were associated with risk of MI or congestive heart failure, compared with metformin monotherapy.
Pioglitazone either as monotherapy or in combination was associated with a significantly lower risk of all-cause mortality during follow-up, compared with metformin (HR 0.69, 95% CI 0.49 to 0.98).There was some evidence of a higher mortality risk with rosiglitazone versus pioglitazone, but the difference was not statistically significant in the fully adjusted model.
"Overall, to date there is no clear or consistent evidence on the possible cardiovascular benefits or harms of rosiglitazone therapy, and results of clinical trials are awaited," the researchers wrote in the journal article.
They acknowledged some of the limitations of the retrospective analysis, including the inability to rule out residual confounding.Fonseca noted other limitations, including the short duration of thiazolidinedione treatment compared with other therapies, the possibility of patients switching to combinations of drugs, and the lack of detailed information on the degree of glycemic control, lipids, and blood pressure.
Tea, Coffee Seem to Protect Against Diabetes
Drinking lots of coffee and tea every day -- even decaf -- might keep diabetes away, new research shows.
In a meta-analysis of 18 studies, drinking three to four cups of coffee per day was associated with a 25% lower risk of diabetes than drinking two cups or less per day (RR 0.76, 95% CI 0.69 to 0.82), according to Rachel Huxley, PhD, of the George Institute for International Health in Sydney, Australia, and colleagues.
There were similar results for decaf coffee and tea.
"If such beneficial effects were observed in interventional trials to be real, the implications for the millions of individuals who have diabetes, or who are at future risk of developing it, would be substantial," the researchers concluded in the Dec. 14/28 Archives of Internal Medicine.
Action Points
•Explain that in a meta-analysis of 18 studies, tea, coffee, and decaf coffee were associated with a significantly reduced risk of type 2 diabetes.
Over the years, a variety of investigators have reported that coffee and tea consumption are inversely associated with type 2 diabetes. To sort out the data, Huxley and colleagues conducted a meta-analysis of 18 prospective studies between 1966 and July 2009 with information on 457,922 patients.
The researchers found a significant inverse relationship between coffee consumption and subsequent risk of diabetes.
Each additional cup of coffee consumed in a day was associated with a 7% reduction in the excess risk of diabetes (95% CI 0.91 to 0.95, P<0.001).
The researchers said the heterogeneity across studies was independent of effects involving gender, geographic region, or the method of diagnosis versus self-report.
Six of the studies reported on the association between drinking decaffeinated coffee and subsequent risk of diabetes.
A pooled summary estimated that those who drank more than three to four cups of decaf coffee per day had about a third lower risk of diabetes than those who didn't drink any decaf (RR 0.64, 95% CI 0.54 to 0.77).
Seven studies also looked at the association between tea and diabetes risk. Again, pooled summaries showed that patients who drank more than three to four cups of tea per day had about a 20% lower risk of diabetes than those who drank no tea (RR 0.82, 95% CI 0.73 to 0.94).
The researchers noted that the coffee findings may be an overestimate due to "small-study bias," and cautioned that any possibility that the association between coffee and diabetes risk is age-dependent warrants further investigation.
The findings suggest that the protective effects of tea and coffee may not be solely related to the effects of caffeine, but rather involve a broader range of chemical constituents including magnesium, lignans, and chlorogenic acids, the researchers wrote.
Tea catechins, for example, may decrease glucose production in the gastrointestinal system, leading to lower levels of glucose and insulin, and green tea in particular may prevent damage to pancreatic beta cells.
The study was limited by the potential for uncontrolled confounding, and because it precludes a more detailed analysis of the effect of adjustment for confounders at an individual level.
Also, it may be limited in its generalizability because only 20% of cohorts were from nonwhite populations.
Lars Rydén, MD, of the Karolinska Institute in Sweden, a spokesperson for the European Society of Cardiology, called the study a "cautiously and carefully conducted meta-analysis."
"There are sometimes claims that coffee may do harm, that it may increase the propensity to cardiovascular disease, but there is no evidence for this," Dr. Rydén said. "The message is that people may drink coffee safely. Coffee from this point of view may actually be of benefit, as well as reducing the risk of getting diabetes - although the reduction is small."
But Rydén noted that other lifestyle issues are far more important than coffee intake.
"Coffee helps, but other things are even more important," he said. "Those who are overweight should reduce their bodyweight by 5% to 10% -- not too much -- and include physical activity, such as a brisk walk for 30 minutes a day. Then those people who are at risk of developing diabetes will reduce this risk by 40 to 50%."
The study was supported by grants from the National Heart Foundation of Australia, the National Health and Medical Research Council of Australia, the UK Wellcome Trust, and Institut Servier, France, and Assistance Publique-Hopitaux de Paris.
The researchers reported no conflicts of interest.
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