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Randomized Clinical Trial Paradigm
By gdpawel at 2012-05-13 00:19
Randomized Clinical Trial Paradigm

The mindset of cancer medicine is to think it's great science to identify the best treatment to give to the average patient is through prospective, randomized trials. We have produced an entire generation of investigators in clinical oncology who believe that the only valid form of clinical research is to perfrom well-designed, prospective randomized trials in which patients are randomized to receive one empiric drug combination versus another empiric drug combination. Do cancer cells like Coke or Pepsi?

All the rigorous clinical trials identified are the best treatments for the average patient. But cancer is not an average disease. Cancer is far more heterogeneous in response to various individual drugs than are bacterial infections. The tumors of different patients have different responses to chemotherapyterm. It requires individualized treatment based on testing the individual properties of each patient's cancer.

There are hundreds of different therapeutic drug regimens which any one or in combination can help cancer patients, with hundreds more drugs in the pipeline. The system is overloaded with drugs and underloaded with wisdom and expertise for using them. We are getting an expanding list of treatments which are partially effective in a minority of patients, ineffective in a majority, remarkably effective in a few, while being enormously expensive. The fastest way to improve things is to match treatment to the patient.

One of the main problems in providing effective chemotherapy is the situation that every patient is unique. Tumors grow and spread in different ways and their response to treatment depends on these characteristics. The amount of chemotherapy that each patient can tolerate varies considerably from patient to patient. Therapeutic protocols currently in use are limited in their effectiveness because they are based on the results of clinical trials conducted on a general patient population, yet no two patients are alike.

Clinical trials test the efficacy, not the accuracy of a drug. Efficacy means producing a desired effect, like tumor shrinkage. Single arm clinical trials provide the tumor response evidence that is the basis for approving new cancer drugs. Metastasistermterm is an organism-wide phenomenon that may involve dozens of processes. It's hard to do replicable experiements when there are so many variables. So, instead, researchers opt for more straightforward experiments that generate plenty of reproducible results (like tumor shrinkage). This gives the illusion that researchers have done something meaningful.

Tumor shrinkage should not be the criteria for approving cancer drugs. A patient responds to therapy when their tumor shrinks, but apparently this has nothing to do with survival. A tumor responds, that is, shrinks a little, then quickly grows and spreads. The cancer comes back with a vengeance and the cancer patient is given a death sentence.

There are tens of thousands of scientists pushing a goal of finding the tiniest improvements in treatment rather than genuine breakthroughs, that fosters redundant problems and rewards academic achievement and publication above all else. The randomized, controlled clinical trial may likely remain the standard for evidence of clinical decision-making in cancer medicine, however, observational methods and systems biology are clearly useful. Even with the importance of clinical trials, it is crucial to work on reducing their inherent limitations, including uncertain generalizations, and to expand the use of the randomized clinical trial paradigm to areas beyond proving biological activity, like diagnostic testing.

Recognizing the reliability of the evidence upon which clinical practice has increasingly come to depend, the time has come for physicians to reassess the value of direct observation, and to trust more readily both the empirical and intuitive discoveries they make each day in their personal experience, even if those discoveries are contradicted by the best available evidence.

As the number of possible treatment options supported by completed randomized clinical trials increases, the scientific literature becomes increasingly vague for guiding physicians. Almost any combination therapy is acceptable in the treatment of cancer these days. Physicians are confronted on nearly a daily basis by decisions that have not been addressed by randomized clinical trial evaluation. Their decisions are made according to experience, new basic science insights, bias or personal preference, philosophical beliefs, etc.

Whatever clinical response that has resulted to the average number of patients in a randomized trial is no indication of what will happen to an individual at any particular time. They are trying to identify the "best guess" treatment for the "average" patient. There is no accuracy, nor any proof that what works for the "average" patient population will work for the "individual."

Until the controlled, randomized trialist approach has delivered curative results with a high success rate, the choice of physicians to integrate promising insights and methods like chemoresponse assays, remains an essential component of this kind of treatment technology.

27 comments | 7428 reads

by gdpawel on Sun, 2012-05-13 00:25
Discrepancies between internal and published analyses of industry-sponsored clinical trials lead to further calls for transparency.

Internal pharmaceutical company documents detailing the planned and completed analyses for clinical trials do not always match the publically available report of the completed trial, highlighting a concerning lack of transparency, according to a study published in this week's PLOS Medicine.

These findings are important as they provide support for reporting standards for clinical randomized controlled trials (such as the universally used CONSORT statement) to recommend transparent descriptions and definitions of all of the analyses performed, including if any study participants were excluded from the analysis; and for pharmaceutical companies to make data available for review.

The authors from the Johns Hopkins Bloomberg School of Public Health in Baltimore in the USA, led by Kay Dickersin and Swaroop Vedula, reached these conclusions by comparing internal company documents (released in the course of litigation against the pharmaceutical company Pfizer regarding the off-label use of the drug gabapentin) to the published reports of the trial.

The authors found that in three out of 10 trials there were differences in the internal research report and the main publication regarding the number of randomized participants. Furthermore, in six out of 10 trials, the authors were unable to compare the internal research report with the main publication for the number of participants analyzed for the beneficial effect of the drug (efficacy) because the research report either did not describe the main outcome or did not describe the type of analysis.

The authors say: "Our findings highlight the need for standardizing the definitions for various types of analyses that may be conducted to assess intervention effects in clinical trials, delineating the circumstances under which different types of analyses are meaningful, and educating those who are involved in conducting and reporting trials such that the standards are consistently adopted."

They continue: "We believe that our findings lend support to policy considerations such as extending mandatory registration to include all clinical trials, making full trial protocols and trial data publicly available through trial registration or other means, and ensuring that regulations pertaining to compulsory reporting of results apply both to trials conducted for regulatory authority-approval and to trials in off-label indications of interventions."

The authors add: "It is time for the balance of power in access to information from clinical trials to be shifted from those sponsoring the trials to the public at large."

Citation: Public Library of Science. "Analyses Of Industry-Sponsored Clinical Trials Show Discrepancies." Medical News Today. MediLexicon, Intl., 31 Jan. 2013

According to the Editors of PLOS Medicine, an initiative from the drugs regulator, the European Medicines Agency, to commit to releasing all of the information from clinical trials once the marketing authorization process has ended, which has been greeted with cautious optimism by proponents of access to data but with much less enthusiasm by the pharmaceutical industry, sparks an interesting debate on the role of medical journals in publishing drug data.

Writing in an Editorial, the Editors state: "As 2013 begins, it is clear that critical times lie ahead for the publishing of clinical trials, which may define the relationship between pharmaceutical companies and the public for many years to come."

The Editors argue: "It is no longer going to be the case, if it ever was, that a trial report published in a journal will be sufficient as the record of a trial - and if journals are not careful, such reports will become unnecessary as well."

The Editors continue: "So in addition to this being a critical time in the relationship of pharmaceutical companies to society in general, it seems that this is a good time to renegotiate the relationship between pharmaceutical companies and medical journals."

As data become more available for reanalysis, the Editors explain that report of a trial sanctioned by the pharmaceutical company and published in a journal will no longer be considered the definitive report of the trial. Instead, this report will become just one part of the large volume of information available around a trial, to be considered in conjunction with all analyses and data.

Over the course of 2013 as EMA defines the terms of reference for the release of data the importance of journal articles' reports of a trial will change. According to the Editors, "Some journals will find this harder to adjust to than others, especially those whose business model is heavily dependent on reprints of pharmaceutical companies' versions of trial reports."

Citation: Public Library of Science. "Call For Greater Transparency In Publishing Information From Clinical Trials." Medical News Today. MediLexicon, Intl., 31 Jan. 2013


by gdpawel on Sun, 2012-05-13 00:32
Robert Nagourney, M.D., PhD.
Medical and Laboratory Director
Rational Therapeutics, Inc.
Long Beach, California

Winston Churchill once said, “Democracy is the worst form of government, except for all the others that have been tried.” I am reminded of this quote by a “conversation” that took place on a cancer patient forum.

A patient wrote that they had requested that tissue be submitted for sensitivity analysis and their physician responded by describing this work as a scam. A scam is defined by the American Heritage Dictionary as slang for a “fraudulent business scheme.”

Continuing Churchill’s thread, we might respond, “that laboratory directed therapies are the worst form of cancer therapy, except for all the others that have been tried.”

Using functional profiling we measure the effect of drugs, radiation, growth factor withdrawal and signal transduction inhibition upon human tumors. Using our extensive database we compare the findings with the results of similar patients – by diagnosis and treatment status – to determine the most active and least toxic drug or combination for each patient.

The test isn’t perfect. Some patient’s cancer cells (about 5 – 7 percent of the time), do not survive the transport and processing, so no assay can be performed at all. Some patients are resistant to all available drugs and combinations. And finally, based on the established performance characteristics of the test, we can only double or in some circumstances triple, the likelihood of a clinical response. This is all well documented in the peer-reviewed literature.

Despite this, it appears that in the eyes of some beholders these strikingly good results constitute a “scam.” So let us, in the spirit of fairness, and academic discourse examine their results.

First, it must be remembered that in 2012 only a minority of cancer patients actually show objective response to available cancer therapies. Five-year survivals, the benchmark of success for advanced disease in oncology (those whose disease has spread beyond the primary site), have not changed in more than five decades.

The highly lauded clinical trial process, according to a study from the University of Florida, only provides a better outcome for a new drug over an old one, once for every seven clinical trials conducted.

More disturbing, only one out of 14 clinical trials provide a survival advantage of 50 percent or greater for the successful treatment group.

According to a study from Tuft’s University, it takes 11 years and more than $1,000,000,000 dollars for a new drug to receive FDA approval.

And in a study published in the New England Journal of Medicine only 8 percent of drugs that complete Phase I (safe for human use) ever see the light of day for clinical therapy. This is the legacy of NCCN-guided, University-approved, ASCO-authorized clinical therapeutics programs to date.

As a practicing medical oncologist I am only too familiar with the failings of our modern clinical trial system. Having witnessed the good outcomes of our own patients on assay-directed protocols whose benefits derive from the intelligent use of objective laboratory data for the selection of chemotherapy drugs, I for one will never return to business-as-usual oncology, regardless of what moniker the naysayers might choose to attach to this approach.

Cancer Clinical Trials are in a State of Crisis

Not good news. And improved treatments will be delayed and patient lives will be lost unless the efficiency and effectiveness of the clinical trials system improves, according to a new report from the Institute of Medicine (IOM), which was commission by the National Cancer Institute to review its Clinical Trials Cooperative Group (CTCG).

At issue are concerns the CTCG program can’t conduct timely, large-scale, innovative trials needed to improve patient care. The average time required to design, approve and activate a trial is two years, and only about half of all trials undertaken are completed. Meanwhile, funding since 2002 had dropped 20 percent, while knowledge about predictive biomarkers and molecular changes has grown.

To remedy the problem, the IOM says the CTCG needs to better respond to emerging scientific knowledge; involve broad cooperation of stakeholders; and leverage evolving technologies to provide high-quality research that can change practices.

Four recommended goals:

- Improving speed and efficiency of the design, launch, and conduct of trials;
- Incorporate innovative science and trial design into cancer trials;
- Improving prioritization, selection, support, and completion of clinical trials;
- Provide incentives to patients and physicians to participate.


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