Clinical Trial Management - Science topic

med watch forms in usa pvpi formsissued by cdsc and in clinical trial cioms form

Dear Clarence Hu , what do you think, are the previous cancer research replicable?

I am not an expert, I do follow some cancer discussions due to the case of my wife (breast cancer invasive lobular...). I find this article very admonishing.

A project aiming to reproduce nearly 200 top cancer experiments found only a quarter could be replicated...

Unreliable preclinical studies could impede drug development later on...

(you may need to copy by answer and paste it with fixed-width font to read it, sorry!)

Patrick Gad Iradukunda The closest to a controlled scientific study is the human challenge studies, of which the two vaccine trials are not. In the human challenge studies, volunteers are deliberately infected with a known strain of the SARS-CoV-2 and kept under closed surveillance environment. One group will receive the vaccine and the other will get the placebo and you monitor the results. Both vaccines did one step closer to this by testing on monkeys and got good results. I believe this is a strong indication that it would work on human as well although in some cases results from monkeys cannot be translated to human. see

I agree with Christophe. Be clear first yourself. It will be very easy then to decide , what to use and why.

Hi a good starting point is this paper:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4521133/ 

I couldn't ascertain if what you mentioned is a hypothetical scenario or an actual one. Assuming this as actual, it is not clear what was the actual intended purpose of the interventional cream, whether the inclusion/ exclusion considers wound characteristics, placebo use. if the subject was enrolled and then conditions progressed on the day of treatment , then it should be reported as an adverse event. If subject is removed from study and placed in standard of care treatment then since you applied the cream you want to know the efficacy is not a good research practice but if you manage to get enough measures that could be used in a tailored statistical approach then at least you would be satisfied. 

Kalpha was .10 and my adjusted percentage was 86%. Thats why I asked if there was a better method.

The Clinical Trials Transformation Initiative is about to complete a project on novel endpoints in clinical trials using mobile technology and are also conducting a project on how related device issues.  We would recommend that you first identify what your endpoint is (by talking to patients and other stakeholders) and then look for the technology to support it not looking for the app first and then using that as an endpoint. Here is info on our project  https://www.ctti-clinicaltrials.org/projects/novel-endpoints we also have a project regarding mobile devices and I have outlined our draft approach for device selection.

Ping me if you would like more info or if I can connect you to our project manager.

Pam

Hope that helps

Hello Laila, 

could you provide some more information about which aspect of the drug should be tested? Are you interested in the kinetics after the administration or in the dynamics, the anesthetic effect related to the administered dose? Is it topically applied or injected. Would you be happy with a "simple" pain score test?

I think there so many different protocols which can be found in literature. So, for an appropriate advise, you should give us more information. 

Best, Thomas

Profa. Jeanetta, mi personal e-mail is cmariamar@hotmail.com

No,i believe not.

The most important part of recruitment is to look at the inclusion exclusion criteria and determine  how that fits with your clinic and geographic target population. Regardless of the population your best promoter is an enthusiastic physician that the client already knows and trusts, who is knowledgeable about the study. Beyond that there are some general guidelines and  principles from marketing that you can use with your target population. For example, if your target population is over 70 then electronic media may be less desirable in promoting your study than print media. If they are under 50 electronic media is generally more desirable. Facebook and tweets are effective in keeping your study in the public awareness. Facebook has an older population than twitter. Reimbursement may be important if you are targeting working adults or parents who need to take time from work.   If it is a healthy volunteer study, local free media may be effective in some areas.

If you are looking for persons with a specific diagnosis you may be able to get a waiver from your IRB to screen your medical records by ICD-10 code and send a letter to potential subjects informing them of the upcoming study.  You could also generate potential participants by contacting local support groups and making them aware of the study. 

 In my geographic area I have a had very poor results contacting other physicians and asking them to refer potential patients. This may be an effective approach in other areas.

For estimating intervention effects in a randomized controlled trial (RCT) there are three main ways: Per-Protocol Analysis restricted to the participants who fulfil the protocol in the terms of the eligibility, interventions, and outcome assessment, As-Treated Analysis comparing the subjects with the treatment regimen that they received not considering which treatment they were assigned and Intention-to-Treat analysis (ITT), evaluation of the treatment groups that includes all patients as originally allocated after randomization. The Consolidated Standards of Reporting Trials, the Cochrane Collaboration, the US Food and Drug Administration, the Nordic Council on Medicine in Europe, and the American Statistical Associations Group have recommended ITT as the way to analyze RCT data.To improve the applicability of study results to individual patients, investigators should improve study design to ensure protocol adherence with minimal loss to follow-up, because this loss at the final recall can result in exactly the same sort of bias as a Per- Protocol Analysis.

Thank you so much!

Neuropsychol Rehabil. 2016;26(1):1-35. doi: 10.1080/09602011.2014.977924. Epub 2014 Nov 10.

Impact of rehabilitation on self-concept following traumatic brain injury: An exploratory systematic review of intervention methodology and efficacy.

Ownsworth T1, Haslam C2.

Author information

1a School of Applied Psychology and Griffith Health Institute , Griffith University , Mt Gravatt , Australia.

2b School of Psychology , The University of Queensland , St Lucia , Australia.

Abstract

To date, reviews of rehabilitation efficacy after traumatic brain injury (TBI) have overlooked the impact on sense of self, focusing instead on functional impairment and psychological distress. The present review sought to address this gap by critically appraising the methodology and efficacy of intervention studies that assess changes in self-concept. A systematic search of PsycINFO, Medline, CINAHL and PubMed was conducted from inception to September 2013 to identify studies reporting pre- and post-intervention changes on validated measures of self-esteem or self-concept in adults with TBI. Methodological quality of randomised controlled trials (RCTs) was examined using the Physiotherapy Evidence Database (PEDro) scale. A total of 17 studies (10 RCTs, 4 non-RCT group studies, 3 case studies) was identified, which examined the impact of psychotherapy, family-based support, cognitive rehabilitation or activity-based interventions on self-concept. The findings on the efficacy of these interventions were mixed, with only 10 studies showing some evidence of improvement in self-concept based on within-group or pre-post comparisons. Such findings highlight the need for greater focus on the impact of rehabilitation on self-understanding with improved assessment and intervention methodology. We draw upon theories of identity reconstruction and highlight implications for the design and evaluation of identity-oriented interventions that can supplement existing rehabilitation programmes for people with TBI.

Work. 2012;41 Suppl 1:4782-9. doi: 10.3233/WOR-2012-0764-4782.

Comparison of randomized and non-randomized controlled trials evidence regarding the effectiveness of workplace exercise on musculoskeletal pain control.

Moreira RF1, Foltran FA, Albuquerque-Sendín F, Mancini MC, Coury HJ.

Author information

1Physical Therapy Department, Federal University of São Carlos, Rodovia Washington Luis, Km 235. Zip Code 13565-905, São Carlos, São Paulo, Brazil. roberta.carreira@gmail.com

Abstract

Evidence synthesized based on randomized controlled trials (RCT) results are recognized as the pinnacle of research excellence; however, the conduction of RCT in workplace environment is not always possible. This study comparatively reviewed evidence from RCT and non-RCT studies in which participants performed workplace exercise for musculoskeletal pain control. Up to February 2011, PubMed, MEDLINE, Embase, Cochrane, PEDro and Web of Science databases were searched. All trials that evaluated workplace exercise interventions for controlling musculoskeletal pain were included. The PEDro scale was used to rate the studies' quality, PRISMA and Cochrane recommendations were applied, and association between frequencies of effect size categories (small, moderate, large) from various outcomes by study type was tested (2x3 contingency table). The search yielded 10239 references in English, from which 21 RCT and 12 non-RCT were selected. Both groups of studies presented methodological flaws including descriptions of randomization, blinding of examiners and absence of intention-to-treat analysis for the RCT, and further absence of controls and blind assessor for the non-RCTs. RCTs had significantly more moderate and large effect size reported in their results compared to non-RCTs (p=0.04). Considering the difficulties in randomizing participants in occupational settings, all studies would benefit from better describing pertinent methodological information.

Hi Daniele

This is not my subject of expertise, but I want to recommend you to get hold of all the material you can find written by the Swedish Professor Henrik Ehrsson.

I hope that this humble and minimalistic helping hand might be of any use to yuo!

Good luck,

Pontus

Dear Vladislavs Sokalsky

I think your question lacks some clarity. If you refer to is a clinical trial and seeks to investigate the effect of medicines, then you are looking for, what is your goal?

By the time these dimensions, hoping to enrich the discussion on the problem.

Sincerely

Dr. Jose Luis Garcia Vigil

Another possible reason is that the larger phase 3 study recruited a more diverse population, so that some patients had genetic risk factors that were not present in the phase 2 population. With recent advances in statistical methods for GWAS (see attached) it may become possible to identify these risk factors based on the combined phase 2 and 3 data and, thus, identify (and exclude) patients who are unlikely to benefit from the study drug.

Check papers by Bernard Munos, and data published by Tufts Center for Study of Drug Development http://csdd.tufts.edu/

I think that the original question is the wrong question. Rather than asking "How do I do this?", you might ask "Is it appropriate to do this?" I believe that it is not. For example, in the National Cancer Institute's CTCAE, anaemia is labelled Grade 2 if the haemoglobin is 8-10 g/dl and Grade 3 if the haemoglobin is 6.5-8 g/dl; death is Grade 5. So, if you give a Grade 2 reaction a weighting of, say, 0.25, a grade 3 reaction a weighting of 0.5, and a grade 5 reaction a weighting of 1, you are implying that four cases of mild anaemia and two cases of moderate anaemia are as bad as one death. Furthermore, the probability of survival with a good quality of life is very high and much the same for Grades 1-4 in this case, which may or may not be so in other cases. The allocation of numbered grades to these categorical descriptions is misleading. If they had been labelled A, B, C, D, and E the question of possible weighting would probably not have arisen.

The short answer to your question is YES.

RCTs have to answer 1 question only:  "does it work? (..in a homogenous group of patients); it answers a question relating to EFFICACY (clinical research).

EFFECTIVENESS, answers the question: "Does it benefit patients?" (the group is more inhomogenous); it is related to "outcomes research"

Efficiency relates to health economy ("how much benefit @ what costs?")

I hope the above helps - good luck!

Reenrollment is effectively a type of crossover. Power is gained from a crossover when comparing two interventions vs. a parallel group design, because intrapatient variability is typically less than between-patient variability for any given outcome and because confounding factors both measurable and not are less apt to influence relevant outcomes differentially between the two interventions within one patient as opposed to between two patients (i.e. signal to noise improves, as measured by effect size and/or variability). There is rich literature on crossover designs. Bear in mind that in a blinded crossover if you re-enroll after interim results are available to the patient or investigator you raise a risk of bias that might not have existed had you planned a crossover de novo. Also, be aware that allowing rerandomization to the original treatment in a 2-treatment crossover effectively causes a loss of power to reject null differences between the treatments vs. a de novo crossover with a planned randomization schedule to each one of two interventions only once.

I read a paper that used untrained acupuncturists as the control arm. It sought to compare strategic vs random placement of the needles.

Dear Anam Zia,

I usually read about Case-Control Studies in Epidemiology rather than clinical trials, as they are usually comparing exposed vs non-exposed and use existing records .

However that said you may find your answer in the following 1998 article:

"An important technique for adding power to a study is to enroll more than one control for every case. For statistical reasons, however, there is little gained by including more than two controls per case."

Now if there is any difference between conducting Epi Case-Control and Clinical trial Case-Control ,if there is such a thing, this may mean there is  difference in ratios. BUT Case-control in Epi is NOT randomized, where as clinical trials ARE randomized.

The following link will help you to see the difference in case/control vs cohort vs clinical trials. Case-Control and Co-hort studies are Observational studies aafter the fact or over time vs Experimental trials known as clinical trials that are randomized.

Since Randomization is the GOLD standard in clinical trials, case -control and co-hort studies, which are not randomized, by definition are not clinical studies. This becomes important when you talk about ratios. 

By contrast a 2005, the summary of a paper entitled: "Compared to what? Finding controls for case-control studies" states "to raise the number of controls when the number of cases is small "[reason #1], to have one good "well selected control group rather than  two or more" to "improve the ability to find important differences" [reason #2].

Author warns: "Although no ideal control group exists, readers need to think carefully about how representative the controls are. Poor choice of controls can lead to both wrong results and possible medical harm." [reason #3]

I hope this helps,

Most Respectfully,

Jeanetta Mastron

Mario provided a very good answer. I can say that the best approach to calculate the sample size for clinical trial is to first understand the hypothesis, study design, and statistical test that we need to apply to test the hypothesis. Second we need to determine all elements that needed for power analysis such as Alpha, Beta, Delta including slandered divination calculation, effect, two sided vs one sided, purpose of testing (superiority, equivalence, or non-inferiority), sample allocation across study groups, data distribution (normal, non parametric, unformed, logistic, or exponential ) and others depends on may different specifications.

I have also very good luck with PASS software, PASS 13. NCSS, LLC. Kaysville, Utah, USA. www.ncss.com.  

You still are not able to obtain INFORMED consent without listing the likely side effects. Unless you want to change the definition of informed, it is not possible, and thus, unethical. We have a long history that demonstrates the problems with allowing partially informed consent in medical research. While the vast majority of researchers may not misuse the wiggle room that partial information provides, the risk is great enough that the benefit is not worth the risk.

I understand your desire to use objective outcomes totally. However, I think we have seen some of the problems with using surrogate outcomes in such areas as cardiovascular medicine and diabetes. Our early obsession with cholesterol numbers, for instance, led to us vastly overestimating the benefit of statins. While the number needed to treat to lower cholesterol with statins is small, the number needed to obtain any real benefit (i.e. prevented heart attacks) is order of magnitudes greater. And for diabetes we have to only look at rosiglitazone for a drug that did a great job of lower blood sugar, while raising the risk of heart disease -  the actual outcome we are trying to prevent in treating type 2 diabetes.

I would also suggest that even phase 3 and 4 trials are, generally speaking, too small to detect most rare adverse effects. Long term pharmacovigilance is the only real way to detect rare outcomes. Of course, we may be talking about very different  levels or rarity. 

Overall, though, I do understand your frustration with the difficulty in knowing which adverse effects are real, and which are psychosomatic or attributable to non-drug effects in a patients life. This is entirely the reason for placebo control, or using an alternate treatment. There are also trials that use an active placebo (one that produces side effects), although finding a suitable active placebo is extremely difficult ( I imagine).

Yes, ethical science is that which provides real information on the benefits and risks of a treatment, but we cannot be more ethical by sacrificing informed consent. It is too important. We have decided, as a society, that the needs of the many are not justification for misusing the few. Your moral calculus may permit this, and I can understand it, but we would need to rewrite our ethics to make partial consent okay.

Thanks Yulia, for these suggestions. I had thought of texting the dentists but identifying a practice manager, nurse or receptionist who could be contacted instead could be a better way of reminding them.

Here is the link to the viewable form but if you need something that will not take 11 pages of paper to print out follow the directions below.

I have the 5D-ASC in the form of an online google survey form for anyone else that wishes to use it paperless. Send me a personal message if you need it and tell me a little bit about your research too! -- Cheers! -- 

It is true that you may consider different sets of populations, depending on the objectives that you plan to evaluate, and as Mohd Kashif has mentioned ther could be one mITT for safety and another for efficacy, and even a tird one for pharmacokinetics. However I would say that this is very unsual, and in fact I have never seen published more than one mITT set for efficacy, which I presume this would be your issue. Nevertheless what it is possible, is to mix mITT, ITT and PP approaches for different analyses. For instance, in a meta-analysis published in 2010 in BMJ (http://www.bmj.com/content/bmj/340/bmj.c2697.full.pdf) it is mentioned that:

"In 12 trials (0.2%) the modified intention to treat approach was used as a secondary analysis. In these studies the primary analysis was by intention to treat (11 trials) and by per protocol (one trial)."

In any case, if you have a good reason for using more than one mITT set you should mention it in advance in your study protocol and SAP and include the rational supporting it as well as evaluate the potential bias on your planned analyses.

Hi Corrine,

In general terms, you will need to keep identifying information on each participant for the purpose of obtaining their data and following up with them. This will need to be kept secure usually on a database that only the research team have access to.

Each participant is usually given an id number linked to their identifying information so that any data collected such as questionnaires or interviews will only show this id number rather than their identifying details. Whoever is in contact with participants would need to be able to identify who they have approached, who has responded, who they need to follow up etc. But the data that is collected from each person should not be linked to that individual, only the number that they are given so that number would appear on the top of questionnaries that they complete so that personal details can be separated from any data collected for analysis. It would be important that you protect their right to anonymity and confidentiality from the research so that others do not know that they are taking part unless they are ok for that to be revealed, for example they consent to take part in an interview or consent for their information to be made available to others.

I'm not sure about the US system specifically but trials and generally very tightly controlled and there are guidelines for their conduct such as the Office for Human Research Protections (OHRP) which would be able to help you identify how to treat different sorts of information. I'm not sure if this answers your question because it was quite broad but if you have anything more specific please let me know.

Best wishes,

Sarah  

What is your hypothesis? It is not clear to me what exactly you're planning to study. You stated initially:

"I want to see (prospective) effect of medication on their disease progression and differences in their body composition"

Now you indicate that you are simply taking some body composition measurements?

You need to be explicit in what you are asking in order to get a helpful response.

Thanks for the information Kristian..Nice question Venkataraju

We have used the PANSS interview in our TIPS research project - a first episode of psychosis project, but clinically we use the PANSS as a way of measuring remission and relapse in our OPUS treatment of first episode psychosis in Region Zealand, Denmark. All our clinical staff are trained in using this instrument, which is applied severel times during the 2 year treatment period. Also we use it as a screening tool for psychosis in our detection team in our TOP project, which combines an information campaign with very quick assessment of people responding on our hotline - usually within two - four days.

As you know drug development is a process.  It includes hypothesis generation and conformation.  The confirmatory step expects to see a well designed and executed clinical trial with prior statement of the null and alternative hypothesis, control of type one error rate, etc.  Your proposal is fine for hypothesis generation but not conformation.  If you see something of interest (if you stare at the sphinx long enough he will wink at you) you need decide if you want to go on to a next step.  It might be an attempt to see if similar findings can be found in other data sets without doing a new randomized trial.  This might be from a post hoc examination of a different clinical trial or from some other form of observational study.  You could immediately consider a high power large clinical trial but the risk is usually considered very high-- confirmation based on your current level of data is a rather long shot.  

So, if you see something it should be considered a lead, a new hypothesis, as if it was fished out of an observational data set that needs confirmation.  You could follow with a carefully designed observational study (see Rosenbaum's book on Observational Studies) and conclude with a randomized clinical trial.  It is great to have leads.  It is a great deal of work to have leads.

Alan

No, a succssful PMA does not cause device reclassification.  Your competitor faces the same requirements as you, presuming the Class III device has not been reduced to a Class II device in the interim.  Your competitor must follow the PMA path if the device remains a Class III device.  The advantage your competitor may have is potential access to your device (once approved) as a predicate device... allowing for a new point of comparison in clinical studies.  However, it also could prove a disadvantage to the competitor if their device does not demonstrate non-inferiority to your device in clinical studies.  To remove this as a possibility, they could instead select the previous gold standard as their predicate device, just as the "first to market" company used in their studies.  An example of a device that was reclassified is digital mammography.  Its original approval as a Class III device was in 2000.  It was later reclassified (2010) to a Class II device, after  several manufacturers were required to follow the Class III guidance.  Hope this helps.

This is an interesting study design question, about a topic I examine and have interest- alternative treatments for anxiety. I applaud you for looking into alternative non-medical treatments for anxiety, and massage studies for anxiety are sparse. The one RCT I found:

Effectiveness of therapeutic massage for generalized anxiety disorder: a randomized controlled trial.

Sherman KJ, Ludman EJ, Cook AJ, Hawkes RJ, Roy-Byrne PP, Bentley S, Brooks MZ, Cherkin DC.

Depress Anxiety. 2010 May;27(5):441-50.

The control groups were thermotherapy and relaxing room therapy. Massage was not superior to the control groups, but all three groups reduced anxiety. Therefore, the effect of massage for anxiety treatment is small at best, no effect at worst. So comparing massage with a gold-standard drug treatment for GAD will most likely not be a fair competition. The issue is that drug treatments for anxiety are for moderate to severe anxiety disorders, while CBT (cognitive behavioral therapy) is for the milder forms of anxiety. So massage falls under the category of CBT, given an important part of CBT and exposure work for anxiety treatment is helping the patient to relax. But before comparing it with CBT, you may want to replicate the study above, given there was no separation from controls. Maybe the study suffered from a low sample size, as there were only 68 study participants dispersed over 3 treatment arms. Maybe the intensity, method, duration or frequency of the treatments were not optimized. I would take a look at replicating the above published study and addressing the possible limitations just discussed.

The regulations for investigational drugs and investigational devices are not the same, though both are regulated by the Food and Drug Administration (FDA).  The regulations, guidances, and FDA warning letters can be found on line at http://www.fda.gov/.

Finally a short note: Another approach would be to search for data on the estimated number of unreported cases for specific diseases and to examine the evidence for the estimation of the number of unreported cases.

In German we use also the term "Dunkelziffer" (engl. dark figure) in public health care. In the figurative sense "Dunkelziffer" refers to a disproportion of diagnosed (or even statistically recorded or reported) disease cases to actual disease frequency.

CRO - clinical research organisations really using Special progect management program.  

We are currently conducting an intervention trial on cancer induced asthenia/fatigue.Evaluation on quality of life scores, depression, sleep quality etc. will be included. We would be glad to share with you the outcome of the study.

Dear Colleagues,

NGF and BDNF may also be considered in coronary atherosclerosis, attached is our related paper on ACS...

George

Dear Thais, you will find a very complete explanation of this and related topics in the book:

Design and Analysis of Non-Inferiority Trials

Rothmann, Wiens and Chan.

Chapman &Hall. 2012.

Dear Christine, changing the primary analysis of the study can only be done prior to database lock in a randomized double-blind controlled study. In an open-label study, however, you might be accused of manipulating the study outcome by changing the primary analysis after the study was over! In any case you have to amend the protocol since the primary analysis is described there. Ethics committee aproval of that amendment appears required. In most cases, however, you would not need to adapt the patient information and informed consent form, which is good for you since the patients may be hard to track after they completed the study. Good luck!

Many issued covered above (sample size adequacy, retention of blind, approval of the relevant ethics/IRB, agreement/concurrence of regulatory bodies) but the most critical in my opinion is that available guidance literature (published studies etc) may have changed the relevance, importance and demonstrated sensitivity of a previous specified endpoint and if that is the case and can be appropriately cited then these data would provide a relevant justification for a change in the endpoint. (However, many regulatory bodies have issues even with adding or changing covariates in a trial). Proceed with caution, obtain input from external experts, prior to making such an amendment.

a true modified release formulation cannot be expected to be bioequivalent to an immediate release formulation. that is like comparing i.v. injection vs. s.c.. if you are the first to formulate your study drug as modified release, a BE study is not suitable unless you just want to know how much your new formulation differes from the conventional one

It really depends on the medication, and the swallowing ability of the patient.

Some medications require an empty stomach, which means they should usually be taken with water. Other medications require a full stomach.

Some medications will be affected by some liquids. For example grapefruit juice should not be drunk by people who are taking some statins (Lipitor, etc), some benzodiazapenes (Valium), Synthroid, and more.

On the other hand, taking an NSAID with milk can reduce gastric irritation.

Patients who have swallowing difficulties can take a thickened liquid, and sometimes will use applesause, pudding, or ice cream to take their meds. As long as there is not a food interaction with the med, this is OK, otherwise you have to use Thick IT power mixed with water to achieve the right consistency.

A pharmacist is your best resource on what medications have food interactions, which should be taken on an empty vs full stomach, and more.

The aim of the inclusion/exclusion criteria is to reduce the number of variables that may influence the effect size of your intervention. Your participant is the child, as it is for them that you are assessing effectiveness (not the family, if I understand your question correctly). You are trying to create a 'pure' perfect population of participants where the only effect difference between your control group and your test group will be due to the intervention. Therefore, if you know that a factor will effect the result of the intervention, you can try to standardise that across your population with you inclusion/exclusion criteria. Thus you might make your inclusion criteria:

- child age 3-5 years

- confirmed diagnosis of .... according to ........

- no co-morbidities

- family members willing/able to concurrently take medication.

Or perhaps more appropriately you might specify the concomitant family treatment as part of your study protocol. As the carer needs to provide informed consent for participation in the research trial, the family will need to agree to also take the medication if they are participating in the trial. You could also add an extra arm to the study that compares the effect of your medication with and without family treatment.

Whichever way, if you suspect that family treatment will alter the medication effect on your subject (the child), then you need to monitor family adherence to their meds as well as the child's in case there is an influence on the actual effect of the medication. Potentially, variable adherence by family members could dilute the actual effect so that your study does not show an effect even if there is a true effect there.

Thank you very much for your response. I will have a look at it !

for a first orientation the qoutient between the highest concentration that is not toxic in normal "control" cell and the concentration that is effective (toxic) in cancer cells should be helpful. For the (long) way to "first in human" I recemmend the EMA guidelines (guideline for cancer attached, basic general guideline in second post)

John,

I was involved in a business that had a budgeting system for clinical trials which had been developed over about 20 years. The system was called Grants Manager from Medidata Solutions and it was for sale only to clinical trial sponsors and CROs.

There is a site-specific budgeting system available from a company called RapidTrials (www.rapidtrials.com) for which there is information on the web site. You may wish to get in touch with RapidTrials to see what they can offer to you. I will also further your inquiry on to them. A good place to learn about budget issues for sites is at the bi-annual meetings of the MAGI organization (www.magiworld.com).

I deal extensively with various trial regulatory environments, including that of India. The recent regulatory changes you refer to - namely the Notification No. GSR 72 (E) Rule (aka, Drugs and Cosmetics (3rd Amendment) Rules of 2013, issued 8 Feb 2013 (I am working from the latest version registered in The Gazette of India, in Hindi and English) - although commendable, are primarily oriented to guard the safety of trial participants and to reform the much criticized (legitimately so) machinery of the Ethics Committees that have been demonstrated to exhibit widespread failure of function, obligation, and accountability in the trial regulatory process. This is much welcomed after a decade of well documented ethical lapses, including

- unethical collusions by - and the regulatory inefficacy of - the Central Drugs Standard Control Organization (CDSCO),

- lack of informed consent,

- inadequate protection from and compensation of clinical trial-related injuries and mortalities (numbering in the thousands),

- clinical trial protocols and guidelines violations including drug approvals without sufficient testing (letrozole being tested on young women for infertility despite overwhelming evidence that it is both embryotoxic and fetotoxic, with high risk of ovarian tumors, liver cancer, and atrophy of the reproductive tract), and

- multiple instances of what has been labeled after investigation as "gross violations of Indian law"

as indicted by the scathing - and scary - report from the Parliament of India’s Standing Committee on Health and Family Welfare (SCHFW), confirmed and reinforced in an extensive undercover investigation by NBC Dateline here in the U.S., and now been investigated by the U.S. FDA. I am personally aware of hundreds of ethical, regulatory, and legal violations over just the past decade.

To the extent that imposing long overdue stricter ethical regulatory guidelines may lead to clinical trials that are better monitored and whose participants are finally receiving critical safeguards, that may improve the quality and objectivity of clinical trials in India, and inspire greater confidence in their results. But we must await the results of further investigations by several Government-mandated panels including additional findings from SCHFW expected to appear shortly to see whether we really arrive at some of the absolutely critical goals I have myself been long advocating, namely this "Ten Point Initiative For Clinical Trials Improvement in India":

1. Construction of an adequate firewall between industry and clinical trial investigators.

2. Removal or massive constraint of corrupt and/or inept contract research organizations. (CROs), essentially foreign middlemen who recruit patients, conduct tests, and analyze data (including the two notorious ones that reviewed a proposal generated by the NBC Dateline expose for the discontinued and discredited Vioxx, which both CROs were shamelessly and recklessly glad to move toward trial and approval!).

3. Assured independent monitoring of conformance of all clinical trial protocols to international recognized standards.

4. Assured diversity of trial populations to avoid the current practice of recruiting from poor homogeneous rural communities.

5. Greater education in clinical trial design, implementation, monitoring, data management, and quality assurance, and funding regulators especially in the Drug Controller of India (DCI) / Drug Control General India (DCGI) and the associated trial watchdog regulatory groups and entities.

6. Second-level monitoring and accountability of the Ethics Committees themselves to assure proper operation and arms-distance protocols.

7. Streamlining of, and improved cross-communication and cooperation between the fractured spectrum of overlapping agencies involved in the clinical trial process (the DCGI and CDSCO cited above, the Indian Council of Medical Research (ICMR), the Drugs Consultative Committee (DCC), the Drugs Technical Advisory Board (DTAB), and the Standing Committee on Health and Family Welfare (SCHFW), among other key players.

8. Increase in the number of Government regulated and funded clinical trial centers with high-quality training in clinical research management and assurance.

9. Fostering of cross-country collaboration initiatives between clinical researchers and medical students in clinical research training, and their overseas counterparts and with overseas senior clinical trial investigators and experts.

10. New funding and training initiatives in translational science/medicine to facilitate the understand and bidirectional enrichment and cooperation between basic scientists and clinical researchers and practitioners, thereby also streamlining the bench to bedside process.

To my mind the real shame of the current clinical trial scene in India falls mainly on the wasted opportunities to empower a generation of gifted young medical students, scientists and researchers who are eager to contribute valuably to the advancement of medical science. India has an extraordinary pool of bright, insightful young medical talent who, I find, too often are given minimal guidance and mentorship, and even less financial support in their endeavors, a loss to all of us, as India could easily become a center of basic medical and clinical excellence, from which we all have a lot to learn as to new and different perspectives in medical thinking, with greater respect and emphasis for natural, not just pharmaceutical, solutions, thus opening up a true Evidence-based Integrative Medicine (eb-IM).

I have great hope that by year's end or shortly thereafter we will begin to finally see a new and reformed properly functioning clinical trial system in India that will join the international community of trial standards at the highest level of integrity. Years may still be required to effect all reforms, but 2013 will see a tremendous move forward towards that goal.

Constantine Kaniklidis

Director of Medical Research,

No Surrender Breast Cancer Foundation (NSBCF)

European Association for Cancer Research (EACR)

Yes, they are very much needed