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Old 05-12-2012, 12:19 PM
gdpawel gdpawel is offline
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Default 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 (flip of a coin) 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?

I doubt that objective reviewers outside of the academic clinical oncology establishment would conclude that the paradigm of performing huge randomized studies to identify the best treatment to give to the average patient has been productive with regard to identifying improved drug regimens. At the end of the day, the only clear conclusion is that there is no clear and meaningful advantage associated with any form of therapy ever examined in these trials.

Clinical trials are used to test the effectiveness of new treatments.

In Phase I trials of chemotherapy drugs, maximum drug safe dosages for humans are established and short term side effects are noted. Most frequently, healthy volunteers are recruited into Phase I trials but sometimes cancer patients are also accepted into the studies.

In Phase II trials, a small number of patients participate – perhaps one or two hundred - and drug effectiveness and a therapeutic range of drug dosages are noted.

Phase III clinical trials are large-scale, multi-institutional studies in which a new drug must prove that it is more effective than existing treatments or at least equally effective, with acceptable toxicities.

Phase IV trials are conducted after a drug has already received FDA approval for use in a certain group of patients. The idea is to see if the drug is effective for patients in other clinical settings or to see how combining the drug with other drugs affects the drug’s therapeutic benefit. Additional information about side effects also is collected.

Standard protocols are developed following lengthy and expensive Phase II and Phase III clinical trials. After so much time and money has been dedicated to this research, many patients (and physicians) believe that the recommended protocols are the best treatment.

However, according to a published report, only 1 of 14 clinical trials improves survival by 50 percent or more. This is often days, sometimes weeks, rarely months and never years (Djulbegovic A, et al. What is the probability that new cancer treatments are better than standard treatments? Proc ASCO, Abs. #6120, 2006).

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 chemotherapy. 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. Metastasis 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.

The one-size-fits-all paradigm is crumbling as individual patients with unique biological features confront the results of the blunt instrument of randomized clinical trials. Not everything we know about effective interventions has been proven through a randomized controlled clinical trial. This cheeky paper in the British Medical Journal gives a systematic review of the randomized controlled trials.

[url]http://www.ncbi.nlm.nih.gov/pmc/articles/PMC300808/
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Last edited by gdpawel : 02-23-2013 at 10:39 AM. Reason: corrected url address
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Old 05-12-2012, 12:25 PM
gdpawel gdpawel is offline
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Default Analyses Of Industry-Sponsored Clinical Trials Show Discrepancies

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

[url]http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1001378
[url]http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1001379
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Last edited by gdpawel : 02-02-2013 at 06:01 PM. Reason: corrected url addresses
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Old 05-12-2012, 12:32 PM
gdpawel gdpawel is offline
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Default The Failings Of Our Modern Clinical Trial System

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.

[url]http://books.nap.edu/openbook.php?record_id=12879&page=R1
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Last edited by gdpawel : 02-08-2013 at 10:31 AM. Reason: corrected url address
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Old 05-17-2012, 03:25 PM
gdpawel gdpawel is offline
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Default Looking beyond Translation — Integrating Clinical Research with Medical Practice

Dr. Robert Nagourney
Medical and Laboratory Director
Rational Therapeutics, Inc.
Long Beach, California

An article in the May 3, 2012, New England Journal of Medicine, (NEJM) from the Mount Sinai School of Medicine and Mayo Clinic, examined the concept of translational research and its largely unfulfilled mission. (Gelijns AC, Gabriel SC. Looking Beyond Translation – Integrating Clinical Research with Medical Practice. NEJM 2012; 366:1659–1661). These investigators reviewed many of the precepts of clinical research and described mechanisms by which outcomes could be improved. Among the points they raised is the need to integrate clinical research with clinical practice to create “patient-centered, science-driven healthcare.”

Despite their academic credentials, Drs. Gelijns and Gabriel recognized that academic medical settings are not always conducive to conducting clinical research. They also describe the lack of incentives for clinical physicians to undertake research studies. They go on to examine the need to refocus medical education onto a science of healthcare delivery. Finally, they decry the performance metrics by which clinical physicians are gauged (tests performed and numbers of patients seen) and contrast that with the equally unsatisfactory metrics for academicians (grants received and papers published). We couldn’t agree more.

While many of the points raised are worthwhile, these authors fail to grasp the fundamental problem at hand. Falling back on the age-old adage that pediatric malignancies have been cured through the clinical trial process, they criticize the adult oncology physicians for their lack of accrual. Their focus on participation in clinical trials as the highest accomplishment to which a medical oncologist might aspire is misguided and misleading. Grinding patients through ill-conceived clinical trials is no way to cure cancer. What are needed are intelligent solutions to complex problems. Complexity by its nature precludes the use of linear reasoning in the solution of problems. So complex is the cancer problem that investigators long since abdicated insights for statistical significance hoping that by throwing enough patients onto protocols, discernible patterns will emerge.

Childhood cancers have not been cured by protocols. They have been cured because they are curable. The average pediatric malignancy manifests a small number of mutational changes. Founder clones identified within these tumors can be eradicated even with the blunt instrument of contemporary chemotherapy. It is not an accident that childhood leukemia is curable, but instead a manifestation of the cells of origin. Childhood ALL, the most common pediatric malignancy is a prime example. Hematopoietic elements by nature are good at dying. Chemotherapy just helps them along.

As we move from pediatric oncology to adult oncology however, we encounter a horse of a different color. There are the common adult tumors like colon and lung that have accumulated a myriad of perturbations over a lifetime of exposures and genetic errors. The pathway back to normality is fraught with hazards and the founder clones are often numerous and diverse.

To meaningfully advance cancer therapeutics we need wholly new conceptual frameworks that connect complex systems to available solutions. Analytic platforms that can reproduce human tumor biology in the laboratory will provide clinicians the targets for treatment, the results they seek and the incentive to participate in clinical trials.

[url]http://www.nejm.org/doi/full/10.1056/NEJMp1201850
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Old 05-27-2012, 11:41 PM
gdpawel gdpawel is offline
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Default The randomized controlled trial: a fiercely defended relic of our ignorance?

In a TheScientist.com article, "Crowdsourcing Drug Discovery," it was commented that for the last 50 years, randomized controlled trials have been the unquestioned gold standard, when in fact they have become a fiercely defended relic of our ignorance in 1962 when Congress empowered the FDA to begin regulating efficacy.

At that time, it was a "best we could do" solution - but now? They take too long, cost too much, are fraught with unsolveable ethical problems that patients and many physicians dislike, and cannot ask the patient-specific molecular questions we now know need to be asked and answered.

Yet, most clinical trialists and the FDA cling to these crude, simplistic tools like an irrational safety blanket. If we can't reach agreement that clinical methodologies must adapt to new knowledge of the biology of disease, and that the way drug development is regulated must rapidly adapt in much the same way, then our ability to accelerate advances in medicine will remain stagnant.

A key point in this article is that the new system should be patient-centric. It has to be something patients will not only tolerate, or enter under duress, but rather a system that makes sense to them personally - even when they are not yet facing a serious or terminal condition. If real patients are left out of the process of change, we will likely end up in the wrong place again.

[url]http://www.f1000scientist.com/article/display/57646/

In a September 18, 2010 NYT article, "New Drugs Stir Debate on Basic Rules of Clinical Trials," it expressed the debate among oncologists about whether a controlled trial that measures a drug’s impact on extending life is still the best method for evaluating hundreds of genetically targeted cancer drugs being developed. Critics of the trials argue that the new science behind the drugs has eclipsed the old rules — and ethics — of testing them.

They say that in some cases, drugs under development, may be so much more effective than their predecessors that putting half the potential beneficiaries into a control group, and delaying access to the drug to thousands of other patients, causes needless suffering. There hasn't been known anyone who hasn't shuddered at the concept that we can't let patients on the control arm cross over because we need them to die earlier to prove a point.

The new wave of drugs in development might require individual evaluation. "We’ll try this for six weeks; if it’s working, great, if not, we’ll shift you right away to the other trial,” said Dr. Jeffrey A. Sosman of the Vanderbilt-Ingram Cancer Center in Nashville. “That’s how I’m going to be able to live with the randomization.”

[url]http://www.nytimes.com/2010/09/19/health/research/19trial.html?hp
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Last edited by gdpawel : 06-02-2012 at 11:44 AM. Reason: correct url address
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Old 08-12-2012, 11:05 PM
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Default Private-Sector Physicians and Pharmaceutical Contract Research: A Qualitative Study

A paper in PLoS Medicine on the increasing ethical concerns over drug company contract research concluded: While a greater number of physicians in more diverse settings are now engaged in pharmaceutical research than were 20 years ago, our data have potentially troubling implications for drug development. We found that the private-sector physicians interviewed identify primarily with the business rather than the science of contract research. In addition, our findings indicate that the private-sector PIs aligned their sense of research ethics with industry—ensuring the responsible conduct of research—rather than foregrounding the interests of research participants. Because these private-sector PIs are largely motivated by financial gain as opposed to making a contribution to science, we suggest that the professional identity of private-sector PIs may inadvertently offer pharmaceutical companies the ability to exert more control over their proprietary information and clinical trial data.

Jill A. Fisher - Center for Biomedical Ethics & Society, Vanderbilt University, Nashville, Tennessee, United States of America

Corey A. Kalbaugh - Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America

Abstract

Background: There have been dramatic increases over the past 20 years in the number of nonacademic, private-sector physicians who serve as principal investigators on US clinical trials sponsored by the pharmaceutical industry. However, there has been little research on the implications of these investigators' role in clinical investigation. Our objective was to study private-sector clinics involved in US pharmaceutical clinical trials to understand the contract research arrangements supporting drug development, and specifically how private-sector physicians engaged in contract research describe their professional identities.

Methods and Findings: We conducted a qualitative study in 2003–2004 combining observation at 25 private-sector research organizations in the southwestern United States and 63 semi-structured interviews with physicians, research staff, and research participants at those clinics. We used grounded theory to analyze and interpret our data. The 11 private-sector physicians who participated in our study reported becoming principal investigators on industry clinical trials primarily because contract research provides an additional revenue stream. The physicians reported that they saw themselves as trial practitioners and as businesspeople rather than as scientists or researchers.

Conclusions: Our findings suggest that in addition to having financial motivation to participate in contract research, these US private-sector physicians have a professional identity aligned with an industry-based approach to research ethics. The generalizability of these findings and whether they have changed in the intervening years should be addressed in future studies.

Citation: Fisher JA, Kalbaugh CA (2012) United States Private-Sector Physicians and Pharmaceutical Contract Research: A Qualitative Study. PLoS Med 9(7): e1001271. doi:10.1371/journal.pmed.1001271

[url]http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1001271#cor1
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Old 08-28-2012, 12:50 AM
gdpawel gdpawel is offline
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Default Autopsies could be beneficial in cancer clinical trials

Autopsies could be beneficial in cancer clinical trials. Response rates (how much a tumor decreased in size) can be inflated when excluding patients who die during clinical trials (evaluable patients).

Patients not considered evaluable are often those who do not get the benefit of an entire treatment plan. The response rate is calculated after removing patients who died from the calculation. This inflates the response rate.

Clinical oncologists often want to publish papers for professional reasons. They need to report on the outcomes of their experiments, but if they had to wait for survival data it could take years until all the data was aggregated.

Response rates give clinical oncologists the opportunity to take a more optimistic look at therapies that have limited success. They can describe results as being complete remission, partial remission or simply clinical improvement.

If they treat all patients for three weeks, they can fairly evaluate the efficacy of a compound, which takes that long (on average) before it can be regarded as effective. If they disregard all patients who died after onset of therapy, and include only those treated three weeks or more, they can improve their data.

Autopsies of the deceased could reveal liver (or other organ) damage. Is this an effect of the drug?

Carcinomatous meningitis (CM) is clinically less common than brain metastasis, having dire consequences for both the quality of life and the overall survival of patients with solid tumors. It supposidly occurs in about 5% of all adult cancer patients, but autopsy studies may double this number, or more.

It is incumbent on the patient and the patient’s professional caregivers to obtain all the information needed to make informed treatment decisions. Are they given that information by this type of cancer medicine?
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Old 08-30-2012, 10:19 AM
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Default Transparency in Clinical Trials

“Over the past five years or so, there has been a gradual increase in the registration of clinical trials into a single database. Although it would be nice to believe that the pharmaceutical industry has embraced the concept of transparency, it is more likely that the FDA Amendments Act of 2007 forced their hand. Without registration of the clinical trial and reporting of the results, the FDA would not consider the data for submission for a New Drug Application.

As Dr. Drazen notes, there are some holes in the existing legislation. Not all studies need be registered. A newly introduced bill into the US House of Representatives would close the loopholes and provide ‘real transparency.’ There are always two sides to every story and the pharmaceutical industry has legitimate proprietary concerns that no doubt will be voiced loudly to members of the House and to the media. It seems to me that this issue represents a wonderful opportunity for the media to inform and educate the public on this important piece of legislation for both sides on the issue.” - Harold DeMonaco, MS

EDITORIAL

Transparency for Clinical Trials — The TEST Act

Jeffrey M. Drazen, M.D.

N Engl J Med 2012; 367:863-864August 30, 2012

In the past few years, registration of clinical trials in a publicly accessible database has become routine. In the United States, much of the impetus for registration derives from the Food and Drug Administration Amendments Act of 2007 (FDAAA). As a result of this law and other actions,1,2 most interventional clinical trials conducted in the United States have been registered at ClinicalTrials.gov, where, in most cases, the trial results must also be reported. The curators of the database have designed a simple tabular format in which the characteristics of the participants enrolled are reported in one table, the key primary and secondary outcomes in a second table, and adverse events in a third table. Journals adhering to the International Committee of Medical Journal Editors guidance for manuscripts submitted to biomedical journals3 have made it clear that reporting results in this fashion will not be considered prepublication of submitted manuscripts.4 One of the purposes of trial registration is to provide a third-party storehouse of trial designs and results. However, for this resource to be of value, it is important that the entire portfolio of clinical trials be in the database.

But there are loopholes in FDAAA that have made it possible for some entities to conduct clinical trials without registering them or reporting the results. On August 2, 2012, Representative Edward Markey (D-MA) introduced into the U.S. Congress the Trial and Experimental Studies Transparency (TEST) Act (H.R. 6272) to close these loopholes. The TEST Act expands reporting requirements under existing federal law by broadening the scope to include all interventional studies of drugs or devices, regardless of phase (i.e., including phase 1), design (i.e., including single-group trials), or approval status (i.e., making no distinction between trials of approved vs. unapproved products); requiring all foreign trials that are used to support marketing in the United States to be registered; mandating results reporting for all trials within 2 years after study completion (including trials of unapproved drugs or devices); and extending results reporting to include the deposition of consent and protocol documents approved by institutional review boards.

This legislation is important. The bill requires that any trial that could be used to support an application for FDA approval be registered in ClinicalTrials.gov and that the results be reported in a timely fashion. It requires that early-phase trials (those in which a drug is initially tested in humans) be registered. Thus, these trials will become public knowledge.

The bill also requires that results be reported whether the drug is submitted for FDA approval by the manufacturer or not. For example, in a case in which a novel therapeutic strategy is associated with adverse outcomes, information about these outcomes would be in the database, even if the product were subsequently abandoned by the manufacturer. That way, if another entity pursued the same treatment approach with a different intervention, the trial designers would be aware of the potential dangers and could develop means for monitoring and mitigating the potential toxic effects.

Consider the disastrous results obtained when studies were conducted with an anti-CD28 antibody.5 All the healthy volunteers injected with the agent fell ill, some gravely ill, within minutes after receiving the treatment. Given that this trial did not need to be registered in a public database, would the data have become public knowledge if the volunteers had not been admitted to a public hospital? By requiring both registration and results reporting, the government would ensure that the data accrued became part of the public record and could guide further work in a given area.

Another provision of the TEST Act would require that trials conducted outside the United States, but used to support an application to the FDA, be registered and that their results be reported in the database in a timely fashion. This provision would ensure that the participants who put themselves at risk to test new treatments see the fruits of their altruism in the public domain. Simply put, a trial could be moved offshore but could not be hidden.

We can make progress in medicine only if people are willing to put themselves at risk to test new diagnostic and therapeutic approaches. To recognize and reward these participants, and in keeping with the Declaration of Helsinki, clinical trials should be conducted in the open, with full public knowledge of the question asked, the intervention tested, and the results obtained. The TEST Act is another step toward this end, and we strongly support it.

REFERENCES

1. De Angelis C, Drazen JM, Frizelle FA, et al. Clinical trial registration: a statement from the International Committee of Medical Journal Editors. N Engl J Med 2004;351:1250-1251

2. International Clinical Trials Registry Platform [url]http://www.who.int/ictrp/en

3. Uniform requirements for manuscripts submitted to biomedical journals [url]http://www.icmje.org/urm_main.html

4. Laine C, Horton R, DeAngelis CD, et al. Clinical trial registration -- looking back and moving ahead. N Engl J Med 2007;356:2734-2736

5. Suntharalingam G, Perry MR, Ward S, et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med 2006;355:1018-1028

Clinical Trial Ethics Are Revised In The Helsinki Declaration [url]http://cancerfocus.org/forum/showthread.php?t=1062

Update: If at first you don’t succeed… trying introducing the bill again. And this is what four Congressmen. In hopes of closing loopholes that allow clinical trial results to go unreported, they have re-introduced the Trial and Experimental Studies Transparency Act, which was first floated last summer but, obviously, went nowhere.

The latest version is really no different. In fact, the press release issued by Ed Markey, spearheading the effort, is almost identical to what was issued in August 2012. In any event, the bill would require that all foreign clinical studies meet the same requirements as domestic trials if they are used to support an application for marketing in the US.

The idea is to update ClinicalTrials.gov. A central reason is that some trial data used to win FDA approval – which may include studies run in other countries – do not have to be registered with the US government database. The bill would, therefore, require such documentation to be submitted, along with informed consent forms and trial protocols.

There is a loophole that can mean results in registered trials are not reported, which may play future trial participants at risk if another drugmaker chooses to develop the same drug but lacks safety data from a previous study. Eighty percent of drugs that entered the US market in 2008 were tested overseas, but many trials were not required to be registered with ClinicalTrials.gov.

There have been several scandals in which clinical trial data for various drugs was not fully disclosed and only became known after litigation or studies, such as meta-analyses, were published in medical journals. This issue has haunted the pharmaceutical industry and, at times, undermined its ability to maintain needed trust with physicians and patients.

[url]http://markey.house.gov/sites/markey.house.gov/files/documents/TEST%20Act%20113th%20as%20introduced.pdf
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Last edited by gdpawel : 05-22-2013 at 10:56 AM. Reason: additional info
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  #9  
Old 09-14-2012, 10:38 AM
gdpawel gdpawel is offline
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Default Statistical reasoning in clinical trials

Gabor D. Kelen, M.D.

Hypothesis testing is based on certain statistical and mathematical principles that allow investigators to evaluate data by making decisions based on the probability or implausibility of observing the results obtained. However, classic hypothesis testing has its limitations, and probabilities mathematically calculated are inextricably linked to sample size. Furthermore, the meaning of the p value frequently is misconstrued as indicating that the findings are also of clinical significance. Finally, hypothesis testing allows for four possible outcomes, two of which are errors that can lead to erroneous adoption of certain hypotheses: 1. The null hypothesis is rejected when, in fact, it is false. 2. The null hypothesis is rejected when, in fact, it is true (type I or alpha error). 3. The null hypothesis is conceded when, in fact, it is true. 4. The null hypothesis is conceded when, in fact, it is false (type II or beta error).

Robert A. Nagourney, M.D.

Scientific proof is rarely proof, but instead our best approximation. Beyond death and taxes, there are few certainties in life. That is why investigators rely so heavily on statistics.

Statistical analyses enable researchers to establish “levels” of certainty. Reported as “p-values,” these metrics offer the reader levels of statistical significance indicating that a given finding is not simply the result of chance. To wit, a p-value equal to 0.1 (1 in 10) means that the findings are 90 percent likely to be true with a 10 percent error. A p-value of 0.05 (1 in 20) tells the reader that the findings are 95 percent likely to be true. While a p-value equal to 0.01 (1 in 100) tells the reader that the results are 99 percent likely to be true. For an example in real time, we are just reporting a paper in the lung cancer literature that doubled the response rate for metastatic disease compared with the national standard. The results achieved statistical significance where p = 0.00015. That is to say, that there is only 15 chances out of 100,000 that this finding is the result of chance.

Today, many laboratories offer tests that claim to select candidates for treatment. Almost all of these laboratories are conducting gene-based analysis. While there are no good prospective studies that prove that these genomic analyses accurately predict response, this has not prevented these companies from marketing their tests aggressively. Indeed, many insurers are covering these services despite the lack of proof.

So let’s examine why these tests may encounter difficulties now and in the future. The answer to put it succinctly is Type I errors. In the statistical literature, a Type I error occurs when a premise cannot be rejected. The statistical term for this is to reject the “null” hypothesis. Type II errors occur when the null hypothesis is falsely rejected.

Example: The scientific community is asked to test the hypothesis that Up is Down. Dedicated investigators conduct exhaustive analyses to test this provocative hypothesis but cannot refute the premise that Up is Down. They are left with no alternative but to report according to their carefully conducted studies that Up is Down.

The unsuspecting recipient of this report takes it to their physician and demands to be treated based on the finding. The physician explains that, to his best recollection, Up is not Down. Unfazed the patient, armed with this august laboratory’s result, demands to be treated accordingly. What is wrong with this scenario? Type I error.

The human genome is comprised of more than 23,000 genes: Splice variants, duplications, mutations, SNPs, non-coding DNA, small interfering RNAs and a wealth of downstream events, which make the interpretation of genomic data highly problematic. The fact that a laboratory can identify a gene does not confer a certainty that the gene or mutation or splice variant will confer an outcome. To put it simply, the input of possibilities overwhelms the capacity of the test to rule in or out, the answer.

Yes, we can measure the gene finding, and yes we have found some interesting mutations. But no we can’t reject the null hypothesis. Thus, other than a small number of discreet events for which the performance characteristics of these genomic analyses have been established and rigorously tested, Type I errors undermine and corrupt the predictions of even the best laboratories. You would think with all of the brainpower dedicated to contemporary genomic analyses that these smart guys would remember some basic statistics.

Why Most Published Research Findings Are False

[url]http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0020124

The panoply of genomic tests that have become available for the selection of chemotherapy drugs and targeted agents continues to grow. Laboratories across the United States are using gene platforms to assess what they believe to be driver mutations and then identify potential treatments.

Among the earliest entrants into the field and one of the largest groups, offers a service that examines patient’s tumors for both traditional chemotherapy and targeted agents. This lab service was aggressively marketed under the claim that it was “evidence-based.” A closer examination of the “evidence” however, revealed tangential references and cell-line data but little if any prospective clinical outcomes and positive and negative predictive accuracies.

I have observed this group over the last several years and have been underwhelmed by the predictive validity of their methodologies. Dazzled by the science however, clinical oncologists began sending samples in droves, incurring high costs for these laboratory services of questionable utility.

In an earlier blog, I had described some of the problems associated with these broad brush genomic analyses. Among the greatest shortcomings are Type 1 errors (described above). These are the identification of the signals (or analytes) that may not predict a given outcome. They occur as signal-to-noise ratios become increasingly unfavorable when large unsupervised data sets are distilled down to recommendations, without anyone taking the time to prospectively correlate those predictions with patient outcomes.

Few of these companies have actually conducted trials to prove their predictive values. This did not prevent these laboratories from offering their “evidence-based” results.

In April of 2013, the federal government indicted the largest purveyor of these techniques. While the court case goes forward, it is not surprising that aggressively marketed, yet clinically unsubstantiated methodologies ran afoul of legal standards.

A friend and former professor at Harvard Business School once told me that there are two reasons why start-ups fail. The first are those companies that “can do it, but can’t sell it.” The other types are companies that “can sell it, but can’t do it.” It seems that in the field of cancer molecular biology, companies that can sell it, but can’t do it, are on the march.
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Last edited by gdpawel : 02-06-2014 at 10:09 PM. Reason: additional info
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Old 09-20-2012, 12:30 PM
gdpawel gdpawel is offline
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Default Randomized Study of How Physicians Interpret Research Funding Disclosures

A Randomized Study of How Physicians Interpret Research Funding Disclosures

Aaron S. Kesselheim, M.D., J.D., M.P.H., Christopher T. Robertson, Ph.D., J.D., Jessica A. Myers, Ph.D., Susannah L. Rose, Ph.D., Victoria Gillet, B.A., Kathryn M. Ross, M.B.E., Robert J. Glynn, Ph.D., Steven Joffe, M.D., and Jerry Avorn, M.D.

N Engl J Med 2012; 367:1119-1127

Abstract

BACKGROUND

The effects of clinical-trial funding on the interpretation of trial results are poorly understood. We examined how such support affects physicians' reactions to trials with a high, medium, or low level of methodologic rigor.

METHODS:

We presented 503 board-certified internists with abstracts that we designed describing clinical trials of three hypothetical drugs. The trials had high, medium, or low methodologic rigor, and each report included one of three support disclosures: funding from a pharmaceutical company, NIH funding, or none. For both factors studied (rigor and funding), one of the three possible variations was randomly selected for inclusion in the abstracts. Follow-up questions assessed the physicians' impressions of the trials' rigor, their confidence in the results, and their willingness to prescribe the drugs.

RESULTS:

The 269 respondents (53.5% response rate) perceived the level of study rigor accurately. Physicians reported that they would be less willing to prescribe drugs tested in low-rigor trials than those tested in medium-rigor trials (odds ratio, 0.64; 95% confidence interval [CI], 0.46 to 0.89; P=0.008) and would be more willing to prescribe drugs tested in high-rigor trials than those tested in medium-rigor trials (odds ratio, 3.07; 95% CI, 2.18 to 4.32; P<0.001). Disclosure of industry funding, as compared with no disclosure of funding, led physicians to downgrade the rigor of a trial (odds ratio, 0.63; 95% CI, 0.46 to 0.87; P=0.006), their confidence in the results (odds ratio, 0.71; 95% CI, 0.51 to 0.98; P=0.04), and their willingness to prescribe the hypothetical drugs (odds ratio, 0.68; 95% CI, 0.49 to 0.94; P=0.02). Physicians were half as willing to prescribe drugs studied in industry-funded trials as they were to prescribe drugs studied in NIH-funded trials (odds ratio, 0.52; 95% CI, 0.37 to 0.71; P<0.001). These effects were consistent across all levels of methodologic rigor.

CONCLUSIONS:

Physicians discriminate among trials of varying degrees of rigor, but industry sponsorship negatively influences their perception of methodologic quality and reduces their willingness to believe and act on trial findings, independently of the trial's quality. These effects may influence the translation of clinical research into practice.

[url]http://www.nejm.org/doi/full/10.1056/NEJMsa1202397#t=articleTop
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