Clinical Trials of Pharmaceuticals - Science topic

Current trend is Nanotechnology based drug delivery systems like nanogels, Hydrogels for wound healing, surgical sprays, Monoclonal antibodies are in high demand in this covid state and many companies are even having patents.

you should look in the fda website, try to search The orange book, then you will find a database in *.txt that could be imported to excel using , and ; as separators from each column.

Hope it works for you, I did it yesterday.

Reverse pharmacology : target-based drug discovery (TDD) is the science of integrating documented clinical/experiential hits, into leads by transdisciplinary exploratory studies and further developing these into drug candidates by experimental and clinical research.

Classical pharmacology, also known as forward pharmacology, or phenotypic drug discovery (PDD), relies on phenotypic screening (screening in intact cells or whole organisms) of chemical libraries of synthetic small molecules, natural products or extracts to identify substances that have a desirable therapeutic effect.

Can you share the way to find the drugs under clinical trail? I want to find the drugs which inhibites alpha glucosidase (alpha glucosidase inhibitors) Omprakash Tanwar

The consistent findings of a lack of benefit of raising the HDL cholesterol level with the use of niacin when added to effective LDL cholesterol–lowering therapy with statins seriously undermine the hypothesis that HDL cholesterol is a causal risk factor. The failure (to date) of cholesteryl ester transfer protein inhibitors, such as torcetrapib and dalcetrapib, to show any reduction in cardiovascular risk despite the marked increases in the HDL cholesterol level associated with these drugs7,8 lends further credence to the notion that HDL cholesterol is unlikely to be causal. Finally, compelling data from a large mendelian randomization study9 also argue that the HDL cholesterol level has a role solely as a risk marker and not a risk factor that merits intervention to reduce cardiovascular events. Although higher HDL cholesterol levels are associated with better outcomes, it is time to face the fact that increasing the HDL cholesterol level in isolation seems unlikely to offer the same benefit

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. 

Sorry I could not find any paper or published article on it.

The test will depend crucially on your hypothesis to be tested.

No in a fixed dose composition similarity wrt BA/BE is more important. 

I am not sure what you are measuring as your endpoint. If it is something like tumor response, and you want to assess potential dose independence I would take the maximum change/effect observed relative from baseline for each group compared to control and see what the value is for each dose cohort. If the effect size for the endpoint in each dose group is the same or not statistically different between each group or above a threshold, then there is evidence of a dose independent effect. You could compare the average of all three groups to each one which should also be internally consistent - no significant difference between the mean of three vs. each individually in terms of maximum effect size. One of the problems with this is it is a post hoc exploratory comparison and also you should consider how to address multiple comparisons because your false positive rate will be increased. 

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.

Hi Ramkumar,

Often the official monograph methods are based on old technology and modern equipment and techniques are superior.  This is probably why you are using an in-house method rather than the pharmacopoeial one?

FDA are likely to accept your in-house method but you will need to conduct a full method development and validation...linearity, range, accuracy, specificity, precision, robustness, ruggedness at various levels across the analytical range dependent on the type of test it is.  The validation report from this work should demonstrate appropriate accuracy and precision of your in-house test and it shouldn't be necessary to set up the pharmacopoeial test in your lab to generate comparative data although this might make your report stronger if you have the capability to easily do so. 

You should make mention of the pharmacopoeial test in your validation report and discuss the sort of accuracy and precision required for assuring the safety, identity, potency of the drug, then discuss how your in-house method is suitable for this purpose and why it is preferable to use your method over the pharmacopoeial one, or you could write up the test requirements in a Design Qualification report to preface your method development and method validation reports.

Avi, your problem looks like a standard situation for the Kaplan-Meier model (i.e. survival analysis with right-censored data). From the KM model you will obtain the (possibly time-dependent) AE occurrence rate, and by integrating it over the total time-span (4 weeks) you will get the estimated ratio of patients with AE by the end of 4 weeks. And this will take the drop-out patients into account.

Well-designed vaccine trials always have specific questions they are designed to answer. You need to know enough about the disease to be able to formulate those questions, but you don't need to know everything about the disease to be able to interpret the results.

In the case of Ebola, the two different trial designs were intended to answer two questions. First, if you are exposed, can vaccination reduce your risk of illness or death? Second, can vaccination of potential contacts prevent the spread of the disease?

Because the vaccines were tested as the number of cases were falling (due to better control of infection) we did not get an answer which is 100% reliable - because there were fewer cases overall. But the data does very strongly suggest that the answer to both questions is yes. That's good enough to know that we should deploy vaccination in an outbreak situation.

So it was worth testing the vaccines, even though when the trials were designed, we did not know about recurrent infection in humans. In the end, it is death and disease that we aim to prevent by vaccination. What our new knowledge adds is that people who are exposed or who fallen ill with Ebola need to be followed up.

In any future outbreak, we also need to test whether vaccinated people can still get a latent infection. From what we have seen, vaccination will probably prevent latent infection but again, but even if it didn't, we would still vaccinate. After all what would you rather have - a latent infection which apparently has a much lower risk of spreading and causes some long-term side effects, or full-blown Ebola infection that is highly infectious and fatal 50-80% of the time?

We don't need to know everything about the disease to know which outcome is preferrable!

Avoid using at all cost, esp in those with any stage of CKD or proteinuria, those on inhibitors of the renin ang system, in obesity, or anyone who may be predisposed to AKI. De novo oligiric AKI can occur even in young patients who have no CKD.

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.

Dear Vini Bains,

You may wish to check out the following thread of Q&A that may help you, where I have posted on ratios in case/control studies

MORE specifically to your question Dr./Professor Ariel Linden also posted  and refers to his RG posted paper that I believe will help you:

"Using balance statistics to determine the optimal number of controls in matching studies"

Respectfully,

Jeanetta Mastron

Thank you so much for giving the valuable reply. Actually I'm going to find the effective permeability of a emulsion. In most of the research articles, Peff was calculated for the drug. So they perfused the drug in the intestine and checked the difference in concentration.

My query is why the researchers are not using any digestive enzyme? Why the gastriointestinal digestion was not accounted during the perfusion study? Some researchers used Pancreatin in the buffer. Is that enough for digestion. As I'm using the emulsion, with protein as a surfactant, I need to digest the material before entering the intestine. Can I follow the Pancreatin digestion..

Kindly suggest a method..

see the paper by virginia le Verche , B Ikiz, A Jacquier, S. Przedborski and D B Re 

J receptor, ligand and channel Research 

4, 2011, 1-22. Glutamate pathway implication in amyotrophic lateral sclerosis: what is the signal in the noise ?

It is best to use the patient's presample as your background. If this shows the same pattern it could be some other drug is causing the interference or the formation of a metabolite.

Dear Stuart, to get a reliable value of IC50, you should assay at least two concentrations above, and two below, the IC50 you expect.  If you're thinking that your coumpond has a 50% activity near 2.5 ug/mL, you might try with 10, 5, 2.5, 1.25 and 0.625.  Remerber to add a positive control group in your assay, it means a group exposed to a drug with known activity.  Also remember that the activity is not linear with the concentration, they are related in a log way (almost always), so, to get a good IC50 value, you must plot the activity versus the log of concentration.

All the best,

Rodrigo

Hi Johannes

It very much depends upon how you structure you manuscript and how you approach the negative findings, i.e. you can present the negative aspect in a "positive" light.  So if your negative result provides an information that will potentially benefit the patient then many journals will accept it, say for example when you are able to show that a substance widely used doesn't have the activity claimed for it.

If you are presenting data from an evaluation of a new chemical entity that becomes a little harder.  However, there are several journals that would consider it, again especially if you write it up in such a way that you can present a positive aspect to the finding.  

I agree with Steven that BMJ accepts negative studies, although they are quite selective anyway on grounds of space.  Alternatively you could submit to BMJ Online, which has a freer editorial policy with regard to the number of manuscripts it accepts (it is not a lower bar for quality though).  Others I have published negative results include PeerJ and F1000Research.  Also some of the BMC journals will accept negative findings so BMC Pharmacology, Trials, etc are defintiely worth a look in addition tot eh other journals specifically targeted at negative findings as suggested by Farhad and Pawan.

As to reviewers, most journals now ask you to recommend names so that may help.  Of course thee can always be a problem with reviewers who don't understand the review process properly and people who just want to show how clever they are but every manuscript runs that risk.  But is you select the right journals there is a good chance of a positive outcome.

Good luck with your search, Ian

To my knowledge at least two antibodies against PCSK9 are now in phase III studies (AMG145 or evolocumab and REGN727or alirocumab) and we have to wait until 2016/7 for the answer whether the reduction of LDL-C corresponds to a similar reduction in cardiovascular endpoints.

At the moment a strong reduction in LDL-C on top of statins has been published for all inhibitors, in some patients even below 50 mg/dl. Whether this strong reduction in LDL-C might lead to other problems is not clear. Some years ago it was discussed whether strong LDL-C lowering by statins might increase the risk for certain cancers but in the meantime this is no longer a topic.

In general for common side-effects pivotal clinical trials will be good places to check, I am not sure where you are looking for the industry supplied information but EPARs for new drug could be one of them. The big issue is estimating incidence rates in rare adverse effects, I do not know of any real repository of reliable knowledge as the way to capture the numerator will be missing. For specific drugs active surveilance systems can give information, but they would be specific and would work best for drugs with relative small exposure, where all are treated in secondary care.

How accurate is your scale, you should not weigh less than 10 mg for each compound. increase the quantities up to a reasonable amount for each excipient to weigh.