Smart Monitor -

MONITORING_PLAN-locked -

SDV -

Regulatory Binder Index Page Device Study.doc -

Regulatory Binder Table of Contents 3-6-2007 -

Regulatory Binder Index Drug updated -

MON FORM 003 Pre Study Qualification Visit Report -

cdisc_glossaryterms_version7.1_final_2008 -

Clinical Research Codes -

ChecklistRegulatoryBinderReview -

eCRF -

demographic form -

Biochemistry -

Exclusion -

inclusion criteria form -

medical history -

physical exam -

randomisation date of visit -

randomisation -

What do I Have to Report to the IRB -

EDC

EDC Revision 1 - Final Version -

Part 2

Good_Clinical_Practice_Part_II -

ICH-GCP part 1

GoodClinicalPracticePartI -

Sample Size

Sample Size and Power in Clinical Research -

Elements in Informed consent

Selene_20TAM_Elements_20of_20informed_20consent_20forms -

Dinesh_20Kumar_20Badyal_Vulnerable_20Clicinal_20Trial_20Subjects -

ICH-CRC-Guide -

Form 1572

It is statement of Investigator

he will abide CFRs accoding to that inv do Research

IND application

IND application -

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

eCRF Training

ECRF Training -

Schedule-Y Indian GCP

SCHEDULE-Y -

ICH-GCP guidelines

ICH GCP guidelines -

FAQ s in clinical Research

Frequently Asked Questions -

protocool -

sample CRF

http://scian.com/news/sciannews91b.pdf

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

Sulfonylureas Linked to Higher Risks of Death and Heart Failure

INDIA BECOMES NO.1 IN CLINICAL RESEARCH

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.

Intravitreal Steroids Show Benefit in Diabetic Retinopathy

Intravitreal Steroids Show Benefit in Diabetic Retinopathy
Intravitreal triamcinolone acetonide reduced progression of diabetic retinopathy more than laser photocoagulation, analysis of data from a randomized trial found.
The cumulative probability of progression from nonproliferative to proliferative diabetic retinopathy at two years was:
• Photocoagulation, 31%
• 1 mg triamcinolone, 29%, P=0.64 compared with the laser group
• 4 mg triamcinolone, 21%, P=0.005 compared with the laser group
Still, corticosteroids cannot be recommended at this time because of the exploratory nature of this analysis and the heightened risk of glaucoma and cataracts, Neil M. Bressler, MD, of Johns Hopkins, and colleagues wrote in the December Archives of Ophthalmology.
Panretinal photocoagulation "markedly reduces" the rate of vision loss in diabetic patients with retinopathy when performed when the eye reaches the threshold for high risk (having three or four high-risk characteristics).
However, the procedure can result in adverse outcomes, such as macular edema with visual loss, and close observation is needed for timely implementation. An alternative treatment therefore would be desirable, the investigators said.
Numerous basic scientific findings support the hypothesis that treatment with an anti-inflammatory agent, such as a steroid, could reduce the risk of retinal neovascularization and progression to the high-risk threshold.
For example, steroids exhibit antiangiogenic properties, and they can downregulate vascular endothelial growth factor.
To test their hypothesis, Bressler and colleagues analyzed data from a randomized trial conducted by the Diabetic Retinopathy Clinical Research Network that included 840 eyes in 693 patients, divided almost evenly by gender.
Participants' mean age was 63 years. Some 95% had type 2 diabetes.
Eyes were randomized to focal/grid photocoagulation or triamcinolone acetonide in a dose of 1 mg or 4 mg as often as every four months.
The original study's primary finding was that photocoagulation was more effective at two years, and had fewer side effects than either 1 mg or 4 mg of triamcinolone in the treatment of diabetic macular edema.
In the exploratory analysis, patients were considered to have had progression if they experienced vitreous hemorrhage, worsening of two or more levels on the diabetic retinopathy scale, or the decision was made to proceed with photocoagulation.
The one-year cumulative progression was:
• Photocoagulation, 21%, P=0.71
• 1 mg triamcinolone, 19%, P=0.03
• 4 mg triamcinolone, 14%, P=0.08
And the three-year cumulative progression was:
• Photocoagulation, 37%, P=0.73
• 1 mg triamcinolone, 35%, P=0.02
• 4 mg triamcinolone, 30%, P=0.07
The investigators noted that during the second year most eyes randomized to the steroid groups did not receive the drug as often as every four months, and fewer than half received the drugs at all during the third year because the study had been closed.
"Theoretically, it is possible the reduction in risk of retinopathy progression may have been even greater if intravitreal triamcinolone had been given more frequently," they wrote.
On the other hand, they suggested, the injections may have been discontinued because the retinopathy was less severe, edema had resolved, and the eyes were generally healthier.
They pointed out that interpretation of the results must be tempered by recognition of the higher rates of cataract extraction at two and three years, respectively, with steroid treatment:
• Photocoagulation, 13% and 21%
• 1 mg triamcinolone, 23% and 35%
• 4 mg triamcinolone, 51% and 64%
Strengths of the investigation include the prospective collection of data and randomization of treatment. Also, some patients had one eye randomized to laser treatment and the other to steroids, which would control for systemic factors that could influence progression.
But the investigators noted that the study also has weaknesses: It was not designed to investigate the progression of retinopathy, data for many patients were censored before completion of the study, and comparative progression of retinopathy was not a primary or secondary outcome of the original design.
Therefore, despite the potential benefits of corticosteroid treatment, investigators concluded that it is not warranted at this time because of the risks, although further investigation of the pharmacotherapy does appear warranted.
"Any treatment to be used routinely to prevent [proliferative diabetic retinopathy] likely needs to be relatively safe because the condition already can be treated successfully and safely with [panretinal photocoagulation]," they wrote.
The study was funded by the National Eye Institute and the National Institute of Diabetes and Digestive and Kidney Diseases.
Bressler has received research grants from multiple pharmaceutical companies, including Allergan. Financial disclosures for all Diabetic Retinopathy Clinical Research Network investigators is available on the group's public Web site, at http://public.drcr.net/FinDisclosures.aspx.

FDA Pleads for More Research on Anemia Drugs

FDA officials used the pages of the New England Journal of Medicine to call for more studies of erythropoiesis-stimulating agents (ESAs) in an effort to improve their safe use.

"It is time to establish, through randomized trials, the optimal hemoglobin target, dosing algorithm, and monitoring approach for patients with anemia from chronic kidney disease," wrote Robert Temple, MD, a top official in the FDA's Center for Drug Evaluation and Research, and colleagues in a "Perspective" piece published online.

They also promised that an FDA advisory committee would "reevaluate" use of these drugs in kidney disease patients sometime this year.

The officials were responding to a series of clinical studies in which efforts to raise hemoglobin levels into the normal range in patients with anemia from chronic kidney disease may do more harm than good.

ESAs, which also include erythropoietin (Epogen, Procrit), have also been found to worsen outcomes in cancer patients. (See Anemia Drugs Increase Mortality in Cancer Patients)

The most recent and perhaps most damning trial in kidney disease patients was reported in October. A 4,000-patient trial of darbepoetin alfa (Aranesp) failed to improve most clinical outcomes compared with placebo and nearly doubled the risk of stroke. (See ASN: No Clinical Benefit for ESA in Anemic Patients with Diabetes, CKD)

That trial, called TREAT (Trial to Reduce Cardiovascular Events with Aranesp Therapy), followed two others that also suggested that risks outweighed benefits of normal-range hemoglobin targets in kidney disease patients: the Normal Hematocrit Study in 1998 and Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) in 2006.

Both trials dosed patients to achieve hemoglobin targets in the range of 13 to 14 g/dL.

Temple and colleagues said that when the TREAT study's sponsor, Amgen, told the agency in 2004 that it was planning the trial, the initial design called for a target of 13 g/dL.

"The FDA expressed concerns to the company that [this] target was excessive, higher than that recommended in ESA labeling and not supported by safety data," they wrote.

The agency gave Amgen the go-ahead only after it negotiated "conservative dosing and monitoring schemes to limit overshoots of the hemoglobin target, oscillations in the concentration, and rapid rates of increase," and made sure Amgen formed an independent data and safety monitoring committee, Temple and colleagues added.

"Despite these measures, the TREAT investigators documented adverse consequences of using an ESA to raise hemoglobin levels," they wrote.

Through a median follow-up of 29.1 months, all-cause death or a cardiovascular event -- including nonfatal myocardial infarction, congestive heart failure, stroke, or hospitalization for myocardial ischemia -- occurred in 31.4% of patients receiving darbepoetin alfa and 29.7% of those receiving placebo (HR 1.05, 95% CI 0.94 to 1.17).

Rates of fatal or nonfatal stroke were 5% in the darbepoietin group versus 2.6% with placebo (HR 1.92, 95% CI 1.38 to 2.68).

Temple and colleagues noted that these event rates translated to "more than one death or cardiovascular event per patient per month in both groups."

On the other hand, TREAT did show that the drug significantly reduced patients' fatigue, need for revascularization, and a composite outcome of death or end-stage renal disease. But, Temple and colleagues wrote, neither TREAT nor the earlier studies provided "convincing evidence of any consistent quality-of-life benefit" to offset the increased risks.

These studies, the FDA officials wrote, "raise major concerns regarding the use of ESAs to increase hemoglobin concentrations . . . above a level intended solely to avert the need for erythrocyte transfusions."

But they acknowledged that more modest increases in hemoglobin might still be beneficial on balance -- hence, their plea for more trials.

"Clearly, more conservative hemoglobin targets -- well below 12 g/dL -- should be evaluated," they argued.

The FDA officials also suggested that "more frequent hemoglobin monitoring and more cautious dosing algorithms," perhaps augmented with computers, may help stabilize hemoglobin levels near these lower targets.

Informed consent documentation

1)subject Arrival time to site
2)To whom sub met
3)Sub was examined by Prinicipal Investigator
PI checked Medical History,Past History must be recorded.
4)PI felt that he was suitable for Particular Study.He has explained all the study related procedures,Study Details,Benifits,Risks of the Study.
5)Note the Version No xxx
Language ?
of ICF given.
6)Give ample time to decide to participate or not
7)Any quries raised by the patient for that what are the answers given by the PI
must be recorded in the IC docmentation.

8)Then take SUB Consent if he is able
9)If the Sub is unable to give consent take LAR. here note the relationship to the sub
Ex:If the sub is father Then LAR has write SON at the Relationship to the sub.
10)If both are illeterates then Take Impartial witness taken
These are documented.

Give one copy to Sub
Note:If a Patient Sign in Telugu ICF When Sub keeps Consent in English PI Add a comment:-Sub is comfortable in signing in English.

definitions of ICH-GCP alone to substantiate each of the roles of an impartial witness and a LAR.1.26 Impartial WitnessA person, who is independent of the trial, who cannot be unfairly influenced by people involved with the trial, who attends the informed consent process if the subject or the subject’s legally acceptable representative cannot read, and who reads the informed consent form and any other written information supplied to the subject.
1.37 Legally Acceptable RepresentativeAn individual or juridical or other body authorized under applicable law to consent, on behalf of a prospective subject, to the subject's participation in the clinical trial.With this it is clear, the situations in which either a LAR / an impartial witness be considered during an informed consent process

if subject is Illiterate who will come into picture LAR or IW or they can overlap in the case ? (tht's the reason i asked the Question ) Generally LAR comes into picture when subject's enrollment is depended upon LAR's consent ( like minors, unconscious subjects, mentally retarded, etc ) & IW comes into picture juz indicating that whatever has been told to subject is same as that written on Informed consent (or patient information sheet) In case of illiterate subjects ( who just cant read & write but is able to take his own decision ) if LAR fits into IW definition, we don't think there is any problem if LAR acts as a IW (sign, date as a IW) & you can document in source note with reason .

If subject is illiterate you will take who's sign along with thumb impression of Subject ..... LAR or IW or LAR will sign as IW ?

excerpt from Schedule Y

ii) Where a subject is not able to give informed consent (e.g. an unconscious person or a minor or those suffering from severe mental illness or disability), the same may be obtained from a legally acceptable representative (a legally acceptable representative is a person who is able to give consent for or authorize an intervention in the patient as provided by the law(s) of India). 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.So, in the case that you have mentioned, I will consider an impartial witness to be present during the informed consent process.

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A Biowaiver means that in vivo bioavailability and/or bioequivalence studies may be waived (not considered necessary for product approval). Instead of conducting expensive and time consuming in vivo studies, a dissolution test could be adopted as the surrogate basis for the decision as to whether the two pharmaceutical products are equivalent. At that time the Biowaiver was only considered for scale-up and post approval changes (SUPAC) to pharmaceutical products.

More recently, the application of the Biowaiver concept has been extended to approval of certain orally administered generic products (www.fda.gov/cder/guidance/3618fnl.htm).

only APIs with high solubility and high permeability and which are formulated in solid, immediate release (IR) oral formulations can be approved on the basis of the Biowaiver procedure. A major advantage of the Biowaiver procedure is the simplification and reduction of time required for product approval, thus reducing the cost of bringing new products to market.

Biopharmaceutics Classification System :

BCS class I: “high” solubility – “high” permeability

• BCS class II: “low” solubility” – “high” permeability

• BCS class III: “high” solubility – “low” permeability

• BCS class IV: “low” solubility – “low” permeability

How is high or low solubility currently defined by HHS-FDA?
The aqueous solubility of a drug substance is considered as high according to the HHSFDA BCS criteria when:
-The ratio of the highest orally administered dose (in mg) to the solubility (mg/ml) is less than 250 ml
-This criterion is met over the pH range 1-7.5 at 37°C
According HHS-FDA guidances, the determination of the equilibrium solubility should be carried out with the shake-flask method (other methods like acid or base titration are permitted, when their ability to predict the equilibrium solubility is justified). The experiments should be carried out a temperature of 37+ 1°C. Further, a sufficient number of pH conditions should be chosen to cover the pH range of 1-7.5 and each determination should be carried out at least in triplicate. The buffer solutions given in the USP are appropriate for the tests, but other buffers are also allowed for the experiments. The pH value of each buffer solution should be checked before and after each experiment. Degradation of the API due to pH or buffer composition should also be reported along with other stability data.
The reason for the 250 ml cut-off criterion for the dose:solubility ratio is that in pharmacokinetic bioequivalence studies, the API formulation is to be ingested with a large glass of water (8 ounces corresponds to about 250 ml). If the highest orally administered dose can be completely dissolved in this amount of water, independent of the physiological pH value (hence the determination over the pH range 1-7.5), solubility problems are not expected to hinder the uptake of the drug in the small intestine.
The other important parameter for the BCS is the intestinal permeability of the drug.

How is high or low permeability currently defined by HHS-FDA ?
According to HHS-FDA a drug is considered a highly permeable, when more than 90% of the orally administered dose is absorbed in the small intestine.
Permeability can be assessed by pharmacokinetic studies (mass balance studies for example), or intestinal permeability methods, e.g. intestinal perfusion in humans, animal models or Caco 2 cell lines or other suitable, validated cell lines. In vivo or in situ animal models or in vitro models (cell lines) are only considered appropriate by HHS-FDA for passively transported drugs. It should be noted that all of these measurements assess the faction absorbed (as opposed to the bioavailability, which can be reduced substantially by first pass metabolism).

Which pharmaceutical formulations can currently be considered for a biowaiver according to HHS-FDA?
In order to be considered bioequivalent according to the HHS-FDA Biowaiver procedure, a pharmaceutical product:
• should contain a class 1 substance

• should be rapidly dissolving, meaning it should release at least 85% of its content in 30 minutes in three different buffers (pH 1.2, pH 4.5 and pH 6.8, composition see multi source document) in a paddle (50 rpm) or basket (100 rpm) apparatus at 37°C and a volume of 900 ml

• should not contain excipients which could influence the absorption of the drug • should not contain a drug with a narrow therapeutic index

• should not be designed to be absorbed from the oral cavity. The reasoning for the above-mentioned dissolution restriction is that when a highly soluble, highly permeable drug dissolves rapidly, it behaves like a solution in the gastrointestinal tract. If this is the case, the pharmaceutical composition of the product is insignificant, provided that excipients which influence the uptake across the gut wall are excluded from the formulation. The API is not prone to precipitation after its dissolution due to its good solubility under all pH conditions likely to be found in the upper gastrointestinal tract. The high permeability assures the complete uptake (> 90%) of the API during its passage through the small intestine. The fast dissolution of the product guarantees that the API is available long enough for the uptake in small intestine (the passage time in the small intestine is approximately 4 hours) and negates any slight differences between the formulations.
Pharmaceutical products containing an API with a narrow therapeutic index should always be tested with in vivo methods, since the risk for the patient resulting from a possible incorrect bioequivalence decision using the Biowaiver procedure is considered too high with these kinds of APIs.
As the BCS is only applicable to drugs which are absorbed from the small intestine, drugs with different sites of absorption (oral cavity) are not eligible for a Biowaiver.
It can be easily seen that the HHS-FDA requirements for classification of APIs and eligibility criteria for the Biowaiver are very strict. In the last decade, several publications and continuing scientific discussions have suggested that the original HHS-FDA criteria for application of the Biowaiver procedure can be relaxed without substantially

WHO high solubility definition
When an API shows a dose/solubility ratio of less than 250 ml at 37°C over a pH range of 1.2-6.8, it can be classified as “highly soluble”. The decrease in pH from
7.5 in the FDA Guidances to 6.8 reflects the need to dissolve the drug before mid-jejunum to ensure enough reserve length for absorption from the GI tract. Furthermore, the dose that is to be used for the calculation is the highest dose indicated in the Model List, even though in some countries other doses may be available on the market.

WHO permeability definition
When an API is absorbed to an extent of 85% or more, it is considered to be “highly permeable”. The permeability criterion was relaxed from 90% in the FDA Guidances to 85% in the WHO multisource document. Some examples of APIs now included in BCS class I that were previously considered to be Class III are: paracetamol, acetylsalicylic acid, allopurinol, lamivudine, promethazine.
Application of these revised criteria has changed the classification of some APIs in the list. Thus, the classifications in the tables attached to this document supercede those in previous publications. As new APIs on the Model List, it will be necessary to classify these according to the revised BCS, so it is anticipated that the Tables will be revised regularily. In addition, some APIs have not yet been sufficiently characterized to assign a BCS classification. As the Tables evolve, it is anticipated that more concrete information will be generated for these APIs as well.
The potential impact of the revised guidelines on registration requirements to establish interchangeability is that a large number of medicines on the EML could become eligible for approval based on in vitro bioequivalence testing in accordance with the dissolution tests prescribed in Section 9 of the Multisource document.

WHO ADDITIONAL CRITERIA FOR APPLICATION OF THE BIOWAIVER PROCEDURE
For all APIs on the EML, it is imperative to consider not only the physical and absorption properties of the API when evaluating the API for Biowaiver, but (as outlined in the Multisource document) to perform a benefit/risk analysis in view of usage at the national level. As an example, in some countries amoxicillin is used primarily for ambulatory patients with mild to moderate upper respiratory tract, urinary tract and other infections. In other countries, amoxicillin might also be used for severe or even life-threatening infections, in which case the risk to the patient of arriving at the wrong bioequivalence decision would be far greater.
Thus, the eligibility criteria according to WHO are
1. The BCS classification (according to the revised criteria) of the API.

2. Risk assessment: Only if the risk of an incorrect biowaiver decision and an evaluation of the consequences (of an incorrect, Biowaiver-based equivalence decision) in terms of public health and individual patient risks outweighed by the potential benefits of the Biowaiver approach should the Biowaiver procedure be applied.

3. Dissolution requirements for the pharmaceutical product: -Very rapidly dissolving (release of >85% of the labelled amount of drug in 15 minutes) in standard media at pH 1.2, 4.5 and 6.8, at a rotational speed of 75 rpm in the paddle apparatus or 100 rpm in the basket apparatus (applies to pharmaceutical products containing Class III APIs).
-Rapidly dissolving (release of >85% of the labelled amount of drug in 30 minutes) in standard media at pH 1.2, 4.5 and 6.8, at a rotational speed of 75 rpm in the paddle apparatus or 100 rpm in the basket apparatus (applies to pharmaceutical products containing Class I APIs and Class II APIs

4. Excipient considerations

The national authority should be mindful that some excipients can influence motility and/or permeability in the gastrointestinal tract. Therefore, the excipients used in the multisource product formulation should be scrutinized. In this regard, the national authority can draw on the experience of formulations which have been approved on the basis of human bioequivalence studies in their own or in other jurisdictions.
If the multisource product under consideration contains excipients that have been used before in similar amounts in other formulations of the same API, it can be reasonably concluded that the excipients will have no unexpected influence on the bioavailability of the product. If, however, the formulation contains different excipients or very different amounts of the same excipients, the national authority may choose not to allow the Biowaiver procedure to be used.
A list of usual and acceptable excipients can be found e.g. at the following website: (www.fda.gov/cder/iig/iigfaqWEB.htm), formulations of some products can be found on national websites of national drug regulatory authorities.

The decision of a national authority to allow a biowaiver based on the BCS should take into consideration the solubility and permeability characteristics as well as the therapeutic use and therapeutic index of the active pharmaceutical ingredient (API), its pharmacokinetic properties, the similarity of the dissolution profiles of the multisource and the comparator products in standard buffers with a pH of 1.2, pH 4.5 and pH 6.8 at 37°C. Data related to the excipient composition of the multisource product is also required. A systematic approach to the biowaiver decision has been established by the International Pharmaceutical Federation (FIP) and published in the Journal of Pharmaceutical Sciences: http://www3.interscience.wiley.com/cgi-bin/jhome/68503813 . They can further be downloaded from the International Pharmaceutical Federation (FIP) website: http://www.fip.org/. These monographs provide detailed information which should be taken into account whenever available in the Biowaiver consideration

BIOWAIVER TESTING PROCEDURE ACCORDING TO WHO
Depending on the BCS classification of the API, based on solubility and permeability characteristics listed in the accompanying Tables, the testing procedure is defined in 9.2.1 of the "Multisource document".

For pharmaceutical products containing BCS class I (highly soluble, highly permeable) APIs:
For rapidly dissolving (as defined above) pharmaceutical products containing BCS class I APIs, greater than 85% dissolution of the labelled amount is required within 30min in standard media at pH 1.2, 4.5 and 6.8 using the paddle apparatus at 75rpm or alternatively the basket apparatus at 100rpm. The dissolution profiles of the comparator and the multisource products should be compared by an f2 > 50 or an equivalent statistical criterion.
If after 15 min more than 85% are released from the comparator and the multisource formulation under the above-mentioned conditions the product will be considered very rapidly dissolving. In this case the products are deemed to be equivalent and a profile comparison is not required.

For pharmaceutical products containing BCS class III (highly soluble, low permeability) APIs:
A biowaiver can be only considered if both the multisource and the comparator product are very rapidly dissolving; 85% or more dissolution of the labelled amount of the API should be achieved within 15min in standard media at pH 1.2, 4.5 and 6.8 using the paddle apparatus at 75rpm or alternatively the basket apparatus at 100 rpm.
Generally the risks of an inappropriate biowaiver decision should be more critically reviewed (side specific absorption, induction/competition at the absorption side, excipient composition and therapeutic risks, etc.) than for BCS class I drugs.
For pharmaceutical products containing APIs with high solubility at pH 6.8 but not at pH 1.2 or
4.5 and with high permeability (by definition, BCS class II compounds with weak acidic properties): These are eligible for a Biowaiver provided that the multisource product:
(i) is rapidly dissolving i.e. 85% or more dissolution of the labelled amount of the API should be achieved within 30 min in standard media at pH 6.8 using the paddle apparatus at 75 rpm or alternatively the basket apparatus at 100rpm, and (ii) The multisource product exhibits similar dissolution profiles, as determined with the f2 value or equivalent statistical evaluation, to those of the comparator product in buffers at all three pH values (pH 1.2, 4.5 and 6.8). For multisource products containing Class 2 APIs with dose:solubility ratios of 250 ml or less at pH 6.8, the excipients should additionally be critically evaluated in terms of type and amounts of surfactants in the formulation.
BCS Dissolution test
Essential Medicines dosage form aluminium hydroxide 500mg N.R. N.A. antacid local effect amiloride hydrochloride 5mg high high 1 9.2.1.1 diuretic

amitriptyline hydrochloride 25mg1 high high 1 9.2.1.1 psychotherapeutic medicine

amlodipine 5mg high high 1 9.2.1.1 antihypertensive medicine Druga Medicines Lista Solubilityb Permeabilityc classd (for biowaiver)e Potential risksf List (EML)g indicationsa
abacavir 200mg high low 3 9.2.1.2
antiretroviral unknown whether poor BA is due to poor solubility or
antiglaucoma poor solubility and acetazolamide 250mg low low 4
no biowaiver
medicine permeability NSAID, antimigraine acetylsalicylic acid 500mg high high 1 9.2.1.1
medicine antithrombotic acetylsalicylic acid 100mg high high 1 9.2.1.1
medicine

aciclovir 200mg high low 3 9.2.1.2
antiherpes medicines chewable tablet; unknown whether poor BA is due to poor solubility

Ethics Committee Approval

EC approval

We give Approval Protocol xxxxxx as in its present form
We have reviewed the study documents xxxxxxxx
xxxxxxxx

If there any protocol deviations,Ammendments,AEs,SAES,SUSAR must inform to EC.

EC has right to onsite vist at any time,Access to Source documents

CRC must collect the EC members list,Standard Operating Procedures(SOP) of EC.

Drug Discovery and Drug Development

Drug Discovery
The process begins with a new idea directed at chemically modifying a disease process. Often the idea relates to developing a drug that will react with a new molecular target within the human body. The idea is usually generated from a thorough knowledge and understanding of disease processes and a continuing involvement with research in the specific therapeutic area of interest.
The target molecule, usually a protein, is isolated or sequestered by biological techniques. Tests are devised that can detect interactions of drug molecules with the target. Tens of thousands of potential drug substances, obtained from massive compound libraries, are then tested against the target in a process called high throughput screening (HTS). Robotics is often used to accomplish this task. HTS yields "hits" - compounds that seem to possess the ability to react with the target molecule. Hits are then studied in detail to determine their exact chemical structure, physical properties, and biological characteristics. Hits that seem suitable from a physical, chemical, and biologic perspective may be termed "leads". A lead compound is one that will be modified to optimize its properties to one that will be the best suited to develop into a medicine - a drug "candidate". The process of modifying a lead compound to obtain one or more drug candidates is called "lead optimization". It uses a technique called combinatorial chemistry to produce a large number of variants of the lead. The variants are again put through high throughput screening to identify substances with the best target activity profile. Each of the best compounds is studied in detail, and one, two, or perhaps three are chosen for further investigation as drug candidates.

The announcement of a drug candidate is a major milestone in the process of drug discovery and development. It marks the end of the discovery phase and the beginning of early development. The announcement is preceded by a patent search, to ensure that the patent on the candidate drug is not already taken by a rival research group, and by patenting all relevant aspects of the discovery.

Early development

It involves laboratory and animal studies. Small animals such as albino rats and mice are the most frequently used to ensure that the investigational product is safe for use in humans. The use of animals has diminished over the years as new bench-based techniques have become available. However, animal testing can be eliminated only for a minority of non-clinical studies and animal toxicology tests are still considered essential to drug development, and are required by government regulators before they will allow human testing. A large proportion of candidate compounds fail animal testing, leading to attrition in the pipeline. Sometimes development efforts have to be abandoned and discovery work re-initiated because all concurrent candidates failed non-clinical testing.
Candidates that prove successful in non-clinical testing are prepared for human testing. A drug formulation such as tablets, capsules, or injection, is produced and tested, and an application, known as the Investigational New Drug (IND) application is filed for regulatory approval in anticipation of permission to conduct human studies.
All potentially unsafe molecules are identified early in laboratory and animal studies so that only those molecules that are relatively safe and effective reach the stage of clinical testing. Government regulators thoroughly scrutinize the results of non-clinical testing and approve, for human testing, only those candidates for which experts feel that the potential benefits in patients will be greater than any potential risk of side-effects.
Human testing begins with Phase 1 studies in a small number of healthy volunteers who are given very small doses of the test compounds in specialized Phase 1 laboratories, in the presence of experienced doctors who have expertise in first-in-man studies. Volunteers are told about the study and all its risks. They are paid a participation fee if they decide to participate. The dose of the test compound is slowly increased over a period of several days till the frequency of minor side-effects reaches the upper end of the acceptable range, or the full dose is reached. The nature of any side effects, and the drug concentration in the body are documented. The investigational compound enters Phase 2 studies only if the potential benefits to patients continue to outweigh the risk of side effects in the opinion of government regulators and independent experts.
Phase 2 studies are conducted in a few hundred volunteer patients suffering from the disease for which the investigational compound is being developed. Patients are explained about the study and the investigational medicine, including potential benefits and all potential side effects. Those who wish to participate in the study are enrolled. Patients receive free treatment, and all blood, urine, and other diagnostic tests are paid for by the sponsor company. However, unlike volunteer subjects in Phase 1 studies, patients are usually not paid for participation in the study. The informed consent document and patient recruitment procedures are reviewed by government regulators and the Ethics Committee of the hospital in advance. Patients are free to withdraw consent at any time during the study. Phase 2 studies help in confirming that the medicine works and in determining the exact dose at which it works best. The new medicine is compared with dummy tablets, usually given on top of standard medicines for the disease so that patients are not harmed even if the experimental treatment does not work.
Many investigational drugs do not work well in these studies. Some are shown to have side effects that occur in more patients than is the case with the older medicines. In many cases the overall cost of using the new medicine works out to be too high when compared to the benefits, and therefore may not sell in preference to older, cheaper drugs. Many investigational compounds are dropped from further development for one or the other of these reasons.

Full Development
Those drugs that are shown to work the best in Phase 2 studies, have the least side effects, and are expected to be the most economically viable, are mass tested in thousands of patients. This phase of drug development is called Phase 3 or full development. The investigational drug is given to many different types of patients - children and the elderly, those with different grades of severity of the disease, those taking other medicines for other diseases, those that need to take the medicine for a long time, and so on. The Phase 3 program is the most expensive part of clinical development. Studies are conducted across multiple patient recruitment sites simultaneously in many countries across continents. All the time, the new medicine is compared with older drugs to confirm that it indeed works better than currently available therapies. The drug may have to be dropped from further development if it is shown that it is only as good as cheaper, older drugs. The sponsor company will want to have such information as early in the development program as possible, so that development can be halted before too much money has been spent.
In the end, only 1 of 10 drug candidates that enter clinical testing at Phase 1 are found to be good enough to justify the high price tag that must be put on the medicine to meet the cost of development. Government regulators review the results of all the studies in great detail and sometimes visit the study sites and cross-question the investigators and sponsor staff. Only when the regulator is fully satisfied with the quality and extent of data is marketing permission given. The investigational drug is then "launched", and becomes a medicine available at the chemist shop or pharmacy.
Even after regulators have allowed the medicine for general use, a strict vigil is maintained. Doctors are required to report any unexpected side effect or suspected health risk with the new medicine as soon as possible to the regulators and the pharmaceutical company concerned. When millions of people start taking a new medicine, new side effects or health risks sometimes come to light. The frequency and extent of these is closely monitored by regulators. Sometimes, warnings and precautions must be added to the product label, and rarely, a drug may have to be withdrawn from the market.
New medicines are very expensive in the early years of sales to pay for the cost of drug development, publicize the benefits of the new therapeutic option, and provide returns to shareholders of the company. Eight to 10 years after launch the patent period expires and the drug is thrown open for other companies to manufacture and sell at low price. Patients are often not able to afford new medicines and, in most countries, the government pays for them and provides them free or at low cost to patients. Health insurance schemes offer to pay the price if the patient holds an appropriate health insurance policy. While government and pharmaceutical companies are doing their best to minimize the costs involved in drug development, the high price of innovative new medicines worldwide remains an unavoidable necessity without which there would be no new medicines. It the price we pay for medical breakthroughs in the early years of their advent so that millions of patients can enjoy their benefits in later years and live longer and healthier lives.

Pre clinical Trails

Preclinical Trails are done before Clinical Trails started.
These include Invitro Trails
Invivo Trails

Invitro Trails They are for genotoxicity studies by using Salmonella typhi TA 98, TA 100, TA 1535 to detect mutagenicity of the test Drug.If the test drug is having mutagenicity test drug increases the number of Histidine revertants.It is carried out with or without S9 enzyme(Metabolic activation enzyme extracted from liver).This is Popularly called Ames Test.

and also we can use E.Coli for Genotoxicity.

Chinese hamster ovary cells are also used for Genotoxicity studies.

Invivo Trails for Safety,to demonstrate the Test Drug is useful to treat certain Disease.
usually done in rats,monkeys

So by using preclinical trails we can get the data of safety and efficacy of Test Drug at Certain extent inorder to confirm we need to do human clinical trails.Then the sponsor applies FDA with IND application.