Neurontin for pain management/neuropathy

[gdpawel]

I've written before that anecdotally, drugs like Neurontin are used off-label. Most drugs are prescribed off-label. One must be cautious that off-label remedies are fully discussed with patients and must not do any harm. A number of practioners like to use Neurontin (gabapentin) for all neuropathy. It is already used for diabetic neuropathy and neuropathic pain and (after a work-up and ruling out other causes) they found this to work. But again, do no harm.

Kay Dickerson, an epidemiologist at Johns Hopkins University, has a new study in the New England Journal of Medicine comparing the outcomes of a dozen studies of Neurontin (gabapentin) to their original protocols. It turns out the researchers working on the Pfizer/Parke-Davis drug changed the endpoints in eight of those trials while they were underway.

MedPage Today has a good recap:

http://www.medpagetoday.com/Neurolog...nagement/16952

From the New England Journal of Medicine:

Outcome Reporting in Industry-Sponsored Industry-Sponsored Trials of Gabapentin for Off-Label Use

S. Swaroop Vedula, M.D., M.P.H., Lisa Bero, Ph.D., Roberta W. Scherer, Ph.D., and Kay Dickersin, Ph.D.

ABSTRACT

Background There is good evidence of selective outcome reporting in published reports of randomized trials.

Methods We examined reporting practices for trials of gabapentin funded by Pfizer and Warner-Lambert's subsidiary, Parke-Davis (hereafter referred to as Pfizer and Parke-Davis) for off-label indications (prophylaxis against migraine and treatment of bipolar disorders, neuropathic pain, and nociceptive pain), comparing internal company documents with published reports.

Results We identified 20 clinical trials for which internal documents were available from Pfizer and Parke-Davis; of these trials, 12 were reported in publications. For 8 of the 12 reported trials, the primary outcome defined in the published report differed from that described in the protocol. Sources of disagreement included the introduction of a new primary outcome (in the case of 6 trials), failure to distinguish between primary and secondary outcomes (2 trials), relegation of primary outcomes to secondary outcomes (2 trials), and failure to report one or more protocol-defined primary outcomes (5 trials). Trials that presented findings that were not significant (P0.05) for the protocol-defined primary outcome in the internal documents either were not reported in full or were reported with a changed primary outcome. The primary outcome was changed in the case of 5 of 8 published trials for which statistically significant differences favoring gabapentin were reported. Of the 21 primary outcomes described in the protocols of the published trials, 6 were not reported at all and 4 were reported as secondary outcomes. Of 28 primary outcomes described in the published reports, 12 were newly introduced.

Conclusions We identified selective outcome reporting for trials of off-label use of gabapentin. This practice threatens the validity of evidence for the effectiveness of off-label interventions.

Source Information

From the Center for Clinical Trials, Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore (S.S.V., R.W.S., K.D.); and the Department of Clinical Pharmacy and Institute for Health Policy Studies, University of California at San Francisco, San Francisco (L.B.).

[gdpawel]

In clinical trials, an event or outcome can be measured objectively to determine whether the intervention being studied is beneficial. The endpoints of a clinical trial are usually included in the study objectives. Some examples of endpoints are survival, improvements in quality of life, relief of symptoms, and disappearance of the tumor.

Changing from pre-specified endpoints once a trial has begun can introduce bias. If endpoints of interest are changed to get better results, the clinical trial will produce biased results which do not inform research. Any changes in endpoints should be declared and explained to the registry of the clinical trial and to any journals that manuscripts are submitted to.

A well designed randomized controlled trial should be in a state of what ethicists call clinical equipoise: uncertainty in the expert community as to the comparative merits of drugs in either arm of the trial (if it weren't in equipoise, the study would be unethical in part because it would knowingly subject some patients with a life-threatening illness to an intervention thought to be inferior).

If researchers are running trials exactly as they are supposed to, 50% of trials will give an inconclusive result in which neither arm of the trial is superior. In another 25% of trials, the "new" drug should prove superior, and in the remaining 25% of the trials, the "old" drug should prove better.

This pattern has been roughly (and encouragingly) established for NCI funded RCTs in a series of papers published by Benjamin Djulbegovic (the latest of which was just published in the March 24 2008 issue of Archives if Internal Medicine).

The field of cancer research has done a lousy job picking candidates; the rate of success going from phase 1 through to registration is around 5%. The big problem, some say, has to do with poor quality animal studies and phase 1 trials.

[gdpawel]

As far as I know, there hasn't been any studies of taxane-induced neuropathy. However, recently, there is a SWOG trial aimed at studying neuropathy. It is a Phase III trial that just started in September 2009 that will involve 380 participants and is available at 180 locations.

Acetyl-L-Carnitine in Preventing Neuropathy in Women With Stage I, Stage II, or Stage IIIA Breast Cancer Undergoing Chemotherapy

http://clinicaltrials.gov/ct/show/NCT00775645

Unfortunately, it excludes those with prior taxane therapy! I came across a Yale School of Medicine study that apparently found a molecular basis for the peripheral pain caused by taxanes. It appears to be caused when the drug binds to a protein and initiates improper calcium signaling. This response leads to side effects such as acute hypersensitivity, slower heart rhythms, tingling, numbness, and other symptoms (PNAS 104: 11103-11108 June 20, 2007)

[gdpawel]

While evidence-based medicine is a noble ideal, marketing-based medicine is the current reality.

http://freepdfhosting.com/ebaef05bfe.pdf

[lizm100]

My experience....all the doctors just love to give you Neurontin for any type of pain. Some like to complement it with Cymbalta. My naturalpath says....that for me it's not the solution. But for others it may be.

[Rich66]

In the non-medical world they refer to this as "moving the goal posts". You know..amongst other FCC regulated words. Hopefully alternatives will surface. Started some here: http://her2support.org/vbulletin/sho...ght=Neuropathy

[gdpawel]

I remember writing five years ago about Bionumerik boosting about its new drug Tavocept, that was aimed at preventing or reducing common and serious side effects, particularly nerve and kidney damage, associated with taxane and platinum drugs. Very little had been accomplished to prevent or reduce chemotherapy-induced toxicities, but they had a new product and began testing it.

BioNumerik Launches Phase III Trial To Confirm Surprising Tavocept Survival Benefit In NSCLC
The Pink Sheet Daily. 2010 Jan 21, S Haley

Buoyed by the discovery that a molecule it set out to test for its chemoprotective qualities appears to confer as much as a 6.7 month survival advantage to the sickest of lung cancer patients, BioNumerik has launched a global Phase III confirmatory trial testing a Tavocept regimen in first-line treatment of advanced adenocarcinoma of the lung, the company announced Jan. 21.

The global trial will enroll patients at 80-100 clinical sites in the U.S., Russia, Ukraine, Eastern Europe and Latin America to test Tavocept (BNP7787) in combination with taxane and cisplatin chemotherapy against taxane and cisplatin alone. The primary endpoint is overall survival, with the goal of establishing the small-molecule drug as a first-line treatment for the most common form of non-small cell lung cancer. BioNumerik expects the study to be fully enrolled by the end of this year.

Tavocept's ability to prevent or mitigate chemotherapy-induced toxicities will be evaluated as secondary endpoints. If the trial is successful, Tavocept will offer oncologists a small-molecule option that is effective in both Asian and non-Asian populations and offers both a survival advantage and reduced side-effects, says BioNumerik CEO Frederick Hausheer.

To substantiate the new Phase III effort, BioNumerik conducted a meta-analysis of data from two smaller randomized, controlled trials of Tavocept in chemotherapy-naive patients with advanced NSCLC treated with taxane plus cisplatin, or chemo alone. The study, published in the December issue of the European Journal of Clinical & Medical Oncology, concludes that among patients with newly diagnosed (inoperable) stage IIIB/IV primary adenocarcinoma of the lung, non-Asian patients had a significant 6.7 month increase in overall survival (p=0.0326) and Asian patients had a "strong non-significant" 4.6 month increase compared to chemo alone (p=0.0720).

The study also found a significant one-year survival benefit in favor of Tavocept in both studies separately and combined. Combined, the studies showed a statistically significant improvement in overall survival (p=0.009) in favor of the Tavocept arms, representing an approximate 7.7 month increase in overall survival, with 68 percent of Tavocept-treated patients alive at one year versus 48 percent of control (p=0.003).

The meta-analysis examined combined survival outcomes for 346 patients in the two trials, in the U.S. and Japan, including 211 patients with primary adenocarcinoma. The result for Asian patients, from a study conducted in Japan by BioNumerik's Tokyo-based development partner ASKA Pharmaceutical, is particular important because of missteps with programs like AstraZeneca's Iressa (gefitinib), which was active in the Asian population, but not in non-Asians, Hausheer pointed out.

New Tool For Measuring Neurotoxicity After Failure

BioNumerik is entering this new round of inquiry armed with a validated instrument for measuring the effects of chemotherapy-induced neuropathy, after Tavocept failed to meet that endpoint in the earlier U.S. study ('The Pink Sheet' DAILY, March 16, 2008).

Chemo-induced neuropathy can manifest itself not only as sporadic neurotoxic events, but also in persistent form, which affects a little over half of patients, explained Hausheer. By looking for neurotoxic events in two consecutive treatment cycles, according to the study design requested by FDA, "we basically were throwing away about 40 to 50 percent of the sample, and that's why it didn't meet its endpoints," he said. The new study will use the Patient Neurotoxicity Questionnaire, which has been validated in randomized trials.

As well as preventing neuropathy, which is largely irreversible once it manifests, Tavocept appears to reduce the severity of renal toxicity from cisplatin, as well as nausea/vomiting and anemia, Hausheer said.

One of the biggest opportunities is in anemia, said Hausheer. While the standard for chemo-related anemia treatment used to be erythropoietin-stimulating agents, safety concerns with ESAs have left a need in the market. Blood transfusions carry a 25 to 30 percent increase in the risk of thromboembolism, Hausheer added.

Not having to worry so much about anti-emetics also appeals to oncologists, Hausheer said. And, if renal toxicity from cisplatin is under control, the regimen could be given in the outpatient setting very conveniently, instead of "having to give patients all that saline hydration," he added.

Privately held BioNumerik is currently discussing Tavocept with potential alliance partners, Hausheer said.

[gdpawel]

This is an article about how drug companies accept huge fines as a cost of doing business for the lucrative off-label market. One of the examples in the piece is off-label claims for Neurontin. Doctors are legally free to prescribe it, but at their own peril (do no harm).

http://www.washingtonpost.com/wp-dyn...905578_pf.html

It has been very routine and well-accepted practice to prescribe drugs in cancer types and disease stages outside of those in which the drugs originally received FDA approval. Generally, however, insurance companies have paid for drugs used outside of FDA-approved settings because the treating physician finds their use in those instances to be "medically necessary." An estimated 60 percent of anti-cancer drugs are used off-label.

However, Medicare has radically expanded its authorization for use of cancer drugs by putting off-label decision making in the hands of compendia writers in the private sector, many of whom are on the payrolls of the companies that make the drugs. The public knows nothing about the financial relationships between drug companies and the physicians, biostatisticians and other scientists who comprise the fourty-four panels that write clinical practice guidelines and determine which drugs, indications and weight of evidence that are included in its compendium.

Compendia claims to use evidence-based methods in their evaluation of therapeutic agents, however, cited literature is often neither the most recent nor the most valid in terms of study design. To give cancer patients confidence that the treatments they receive are worth the cost, the compendia used to justify payment for the off-label use of anti-cancer drugs should adhere to the highest standards of clinical evidence and arrive at their conclusions in a fully transparent manner that includes full disclosure of "conflicts of interest."

All drug reps have to do is bring into the doctor a Compendia report and then it is off to the races! How goes Medicare, goes the private insurance companies.

I'm all for cancer patients, particularly at end-stages, receiving these needed drugs. My personal belief in having additional support of drug patient-specific activity, as determined by extensive laboratory pre-tests to improve patient outcomes, could very well bolster an argument for off-label use of specific cancer drugs, with no economic ties to outside healthcare organizations; recommendations made without financial or scientific prejudice.

[Rich66]

Craaazy thoughts here:
Government oversight should either rule an application too hazardous to remain legal or leave it up to the discretion of doctors who may already be gunshy about off label due to potential malpractice claims.
Likewise, doctors should have no way to profit more/less or receive/lose perks based on drug selection.