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Hey, friends! Let's try out ourselves how competent we're & how much competencies can be turned into our practice.. .. .. .. try HERE
Sunday, December 23, 2007
Monday, December 17, 2007
"Losers make promises they often break. Winners make commitments they always keep. "
This is one of the quotes of Denis Waitley. Do you know him?
He's one of the most sought after keynote speakers & productivity consultants in the world today.
In this post , I don't focus on him, but I wanna give you a link where you can find an inspirational reading on the topic initiated with this quote entitling "The thirteen most important characteristic traits for success".
I swear it can lighten your way to get valuable assets in life.
Sunday, December 9, 2007
Desperate situation calls for desperate decision.
Yeah! That's right! However enthusiastic about something you are, desperate situation calls for desperate decision. Can you accept that it works out on the way of life ?
It alerts us to go through the life practically & not look for unreachable things.
Desperate decision doesn't mean only the last choice of attempts , but the best in facing real life.
Doctors most often come to such kind of decision.
An author from the website I recently visited said:
" There is no magic in developing the ability to be decisive. It is simply a mindset; a mental attitude that comes with practice and persistence." And she gives 9 steps to be decisive.
Atleast it'll leave you something to think.
You know how new oncological chemotherapeutic drugs are approved?
It's really interesting. It's a part of what written in Textbook of Medical Oncology (I don't know which edition it is) & just extracted from the chapter of Clinical Pharmacology. To get the full coverage, I've copied it as itself:
Drug Development:
Clinical Trial Design
Nonclinical Drug Testing
New compounds are discovered primarily by two means. First, there is rational design of new therapeutic agents. When a target is known, drugs can be tailored to fit the target. Second, compounds are discovered as a result of high throughput screening in which multiple
compounds with unknown activity are tested against a series of cell lines. Those with the best activity are selected for further development. From either source, new agents with promise are tested in vitro to determine whether the drug can kill cancer cells. If successful, in vivo testing is performed to determine whether the drug kills only cancer cells. During in vivo testing, the schedule of administration and route of administration are determined. Subsequently, drugs are formulated for the optimum route of administration (oral or intravenous) and the administration schedule is again optimized (daily, weekly, infusion, etc). Although schedules are
often based on expected toxicities, mechanisms of action, and animal studies, patient and physician convenience is also a priority. If the agent yields positive results in nonclinical
testing, clinical trials are performed. Based on toxicology studies involving animals, a starting dose is determined for phase I clinical trials using one of two standard techniques. The more common method is to take one-tenth of the lethal dose that kills 10% of the most sensitive species. An alternative strategy is to use one-third of the toxic dose low (defined as the lowest
dose of a substance at which any toxic effect is produced). Once the phase I dose has been selected and appropriate regulatory measures have been met, phase I clinical trials are then performed.
Phase I Trials
The primary goals of a phase I clinical trial are to determine the maximum-tolerated dose and the recommended phase II dose. Secondary goals are to determine the optimal administration schedule, the toxicity profile of the agent, and the pharmacokinetics and pharmacodynamics, as discussed previously, and to observe for any clinical activity. Traditionally, patients who enter phase I clinical trials have advanced cancer. With newer nontoxic agents, phase I research is now performed more often in healthy volunteers,
but ultimately, patients with cancer are enrolled. Generally, these patients have no other treatment options; clinical trials are typically a second-line or a third-line choice for
patients with metastatic cancer. To be eligible, patients must have a good performance status and a relatively normal endorgan function so that adequate pharmacology can be determined.
Clinical benefit is seen in approximately 5% of patients enrolled in phase I clinical trials.10
Classic phase I design for cytotoxic chemotherapy agents has been developed largely empirically. In the classic design, three patients receive each dose level. Doses are
escalated using a modified Fibonacci escalation scheme. Cohorts of three patients are expanded if toxicities occur. Pharmacokinetic measurements are typically obtained for all patients, as are toxicity and tumor assessment. In newer trial designs, fewer patients are treated at low,
theoretically inactive, doses. One popular trial design is a rapid dose-escalation scheme in which only one patient is enrolled at each dose level until a particular level of toxicity occurs. In this scheme, doses are often increased by 100%. One of the negative aspects of this trial design is the
limited pharmacokinetic and pharmacodynamic opportunities with only one patient per dose level. In another design, assignment of dose is pharmacokinetically driven. This design is based on the immediate readout of the pharmacokinetics in an individual, and subsequent doses are chosen based on what was found in preceding patients. Typically, phase I clinical trials are performed for patients with multiple tumor types, but there is an increasing trend to perform phase I trials for patients with single tumors, particularly when clinical efficacy is a necessary
early endpoint. With agents that are not expected to be overly toxic or when clinical effects are expected before toxic effects are likely to develop, there are other designs that can be used. In this situation, clinicians prefer to use a validated pharmacodynamic endpoint. This practice is
appropriate when the investigator expects to see the Clinical Pharmacology efficacy of an agent before toxicity appears and when higher doses will be no more effective than lower doses.
However, there are few validated molecular endpoints and these types of trials have not been traditionally recognized by a regulatory body. As enhanced molecular biology leads
investigators to conduct such trials, one can predict an increased determination of the optimum biologic dose instead of the maximum tolerated dose. Phase I clinical trials involving agents in combination have the added emphasis of evaluating the interaction between the two agents. This is particularly important when there might be a pharmacologic interaction resulting
in a substantial change in the toxicity profile. Phase IB clinical trials are simply dose-escalation trials in which some measure of clinical outcome is included. Following the completion of phase I clinical trials,
investigators should be able to determine if there is
• Acceptable drug-related toxicity
• Appropriate administration schedule
• Any anticancer activity
Investigators are discouraged from making decisions, although they frequently do, about performing subsequent studies (a so-called go/no-go decision) on the basis of results from phase I clinical trials alone.
Phase II Trials
The primary goal of phase II clinical trials is to determine the efficacy of an agent. Somewhat unique to oncology, the single-arm phase II trial, in which the complete and partial response rates are determined, is used to make phase III design decisions. Typically, a fixed dose and
schedule of the therapy are selected and patients have only one tumor type. The ideal setting is one in which all the patients have the same characteristics and have received the same previous therapy. All patients begin receiving the study drug at the same dose level and typically all patients have measurable disease. The primary endpoint is the response rate to confirm the toxicity profile, which was first defined in the phase I clinical trial. Phase II trials also offer
an opportunity to explore molecular endpoints. The choice of tumor type is based on preclinical and early clinical research, as well as the molecular biology of the mechanism of the agent’s action. Many studies involve patients who have untreated metastatic cancer, but some
involve patients who have highly refractory tumors, so that efficacy can be evaluated quickly and regulatory approval can be obtained. Phase II clinical research is typically the standard point at which decisions are made about the subsequent development of a given compound. If no
clinical activity has been observed in phase II studies, the development of the drug is usually not continued. The statistical design for a phase II single-arm trial relies on a two-step trial design. Based on the degree of activity that is expected or desired, an initial small number of patients (typically fewer than 20) are enrolled in the trial. Depending on how many patients in this initial subset have a complete or partial response, a decision is made as to whether patient accrual will continue to complete the trial. This design limits the number of patients exposed to “inactive” agents. However, newer cytostatic agents would (and have) fail this test. Therefore, there is an
increased emphasis on randomizing phase II clinical trials, particularly when cytostatic agents are being tested. Timeto- disease progression endpoints are important in these studies. Unfortunately, few have succeeded with this development pathway.
Phase III Trials
The ultimate goal of phase III clinical research is either to gain approval of a new agent by a regulatory body or to displace the current standard of care. These trials are large, ranging from as few as 300 patients to as many as several thousand patients. By definition, these trials are randomized clinical studies. The design and size of each trial hinges specifically on the selected endpoints. The goldstandard endpoint is survival, recognized by all regulatory agencies. However, response rate, time to disease progression, quality of life, and other nontraditional endpoints have been incorporated into phase III clinical trial designs and have provided support to the approval process of many new agents in oncology. Examples include gemcitabine for
pancreatic cancer and capecitabine for first-line treatment of colorectal cancer.
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