Archive for the ‘Off-Label use’ Category

Metformin and cancer: Doses, mechanisms and the dandelion and hormetic phenomena.

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Posted 09 Apr 2012 — by James Street
Category Metformin, Off-Label use

In the early 1970s, Professor Vladimir Dilman originally developed the idea that antidiabetic biguanides may be promising as geroprotectors and anticancer drugs (“metabolic rehabilitation”). In the early 2000s, Anisimov’s experiments revealed that chronic treatment of female transgenic HER2-/neu mice with metformin significantly reduced the incidence and size of mammary adenocarcinomas and increased the mean latency of the tumors. Epidemiological studies have confirmed that metformin, but not other anti-diabetic drugs, significantly reduces cancer incidence and improves cancer patients’ survival in type 2 diabetics. At present, pioneer work by Dilman & Anisimov at the Petrov Institute of Oncology (St. Petersburg, Russia) is rapidly evolving due to ever-growing preclinical studies using human tumor-derived cultured cancer cells and animal models. We herein critically review how the antidiabetic drug metformin is getting reset to metabolically fight cancer. Our current perception is that metformin may constitute a novel “hybrid anti-cancer pill” physically combining both the long-lasting effects of antibodies-by persistently lowering levels of blood insulin and glucose-and the immediate potency of a cancer cell-targeting molecular agent-by suppressing the pivotal AMPK/mTOR/S6K1 axis and several protein kinases at once, including tyrosine kinase receptors such as HER1 and HER2-. In this scenario, we discuss the relevance of metformin doses in pre-clinical models regarding metformin’s mechanisms of action in clinical settings. We examine recent landmark studies demonstrating metformin’s ability to specifically target the cancer-initiating stem cells from which tumor cells develop, thereby preventing cancer relapse when used in combination with cytotoxic chemotherapy (dandelion hypothesis). We present the notion that, by acting as an efficient caloric restriction mimetic, metformin enhanced intrinsic capacity of mitotically competent cells to self-maintenance and repair (hormesis) might trigger counterintuitive detrimental effects. Ongoing chemopreventive, neoadjuvant and adjuvant trials should definitely establish whether metformin’s ability to kill the “dandelion root” beneath the “cancer soil” likely exceeds metformin-related dangers of hormesis.

Cell Cycle. 2010 Mar 21;9(6)

Can a Diabetes Drug Prevent Cancer Death?

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Posted 18 Feb 2012 — by James Street
Category Metformin, Off-Label use
Life Extension Magazine February 2012
As We See It
By James Saftig
Can a Diabetes Drug Prevent Cancer Death?

With its near-perfect safety record, low cost, and favorable side-effect profile, the anti-diabetic drug metformin is one of the few FDA-approved drugs Life Extension® recommends its members should take every day.

Between 1990 and 2011 alone,1 over 1,000 published studies have yielded confirmatory data on its numerous anti-aging properties, from weight loss and glucose control to cardiovascular disease and cancer defense.

As the medical establishment continues to ignore this mounting body of evidence, ongoing research powerfully validates our position.

In one of the largest studies of its kind, a team of scientists analyzed cancer risk among 8,000 diabetics treated with metformin.2 Over a 10-year period, they observed a 54% lower incidence of all cancers compared to the general population.

Metformin not only exerted a major protective effect against cancer development, but those who developed cancer exhibited a significantly higher survival rate, including those with malignant cancers of the lung, colon, and breast. Of equal significance was the finding that the earlier the metformin regimen was initiated, the greater the preventive benefit.

Given that diabetics are predisposed to a horrifically wide array of cancers—of the breast, colon, liver, pancreas, kidney, endometrium (uterine lining), among others3-5—these results have profound implications for all maturing individuals.

In this article, the most recent data supporting metformin’s anti-cancer mechanisms are detailed. You will learn of its specific mechanisms of action, which shed further light on the link between obesity, diabetes, and cancer initiation. You will also discover how metformin induces cancer cell death at their earliest stages of development via metabolic pathways that also promote weight loss and optimal glucose control.

Metformin Slashes Cancer Risk in Multiple Clinical Trials

The study cited in the introduction of this article (54% lower risk of cancer) was of such medical importance as to merit an accompanying editorial by noted cancer epidemiologist Bruce B. Duncan, MD, PhD.6 Duncan observed that this was the most compelling amongst a rapidly growing set of studies, all suggesting that metformin might induce profound effects in preventing a wide range of cancers while improving prognosis in people who do develop malignancies.6

Additional supportive studies validate these findings.6 In a cohort study of more than 12,000 patients, metformin users died of cancer 30% less often than those taking another category of drug called sulfonylureas (including DiaBeta® and Glucotrol®).6,7 Of equal and even greater significance, people taking insulin had a 90% greater death rate than the metformin users in that study.6

In a second study of different design, people taking metformin for diabetes control for more than 36 months had a 72% lower risk of developing cancer than those on other regimens.6,8 Similarly, in a third study, metformin users had a 62% lower risk of developing cancer, compared with those who had never used metformin.6,9 Of significance, that study also showed an increased risk of cancer in people who were taking insulin or oral antidiabetes drugs other than metformin.

There’s additional evidence that metformin not only prevents cancer from developing, but also helps to improve the prognosis in patients who do develop tumors. In one study of breast cancer patients on chemotherapy, 24% of those who were also taking metformin had a complete response rate, compared with just 8% for those not taking it.6,10 As a result of these “incidental” findings, scientists have initiated several clinical trials to examine the impact of metformin as formal additional treatment for breast and other cancers.6,11

Numerous recent studies further support a close association between metformin use and substantially reduced cancer incidence, along with improved survival.12-16

These observations raise the question, “Why should a diabetes drug protect against cancer?”6

The answer is both simple and surprising.

Diabesity and Cancer Initiation: How Metformin Works

Diabesity and Cancer Initiation: How Metformin Works
Cancer Cell

Years of clinical analysis have confirmed the link between obesity and diabetes, conditions whose co-occurrence has given rise to the term diabesity.

Diabesity is a direct causative factor in the development of a wide range of cancers. Diabetics have as much as a 41% increased risk for virtually all cancer types compared to healthy people. Elevated blood sugar alone increases the risk of certain cancers, including those of the kidney, pancreas, and skin (melanoma).6,17,18

Obesity increases cancer risk for more than a dozen different cancers.6 A 59% increase in cancer risk has been documented for every 5-unit increase in body mass index (BMI) alone.6,19 Studies show that obesity is responsible for up to 20% of cancer deaths in women.20

The link between diabesity and cancer points to the underlying mechanisms of action by which metformin works as a cancer-preventing agent.

Metformin operates at the molecular level by activating adenosine monophosphate-activated protein kinase or AMPK, a molecule essential to life. AMPK or its molecular analogs are present in virtually all living organisms.6,21 It also happens to be intimately involved in cellular processes whose dysregulation play a central role in both diabesity and cancer initiation.

Diabetes and obesity result from various metabolic derangements. Cancer results from disordered regulation of cell growth. AMPK is critical to normal regulation of both metabolism and cell growth, as a result of millions of years of evolutionary development.6

As a fuel-sensor and metabolic master switch, AMPK recognizes and responds to changes in cellular energy levels, determining how fats and carbohydrates will be used in storing or utilizing energy.6 In metabolic terms, AMPK tells cells to conserve and generate new energy stores. In so doing, it lowers sugar output from the liver, increases glucose uptake from the blood, maintains insulin sensitivity, and ultimately lowers blood sugar.6,21

AMPK exerts similar effects in terms of regulating cell growth and replication, instructing cells to conserve energy, slowing and often shutting down aberrant cell growth entirely. In essence, when AMPK is activated, incipient cancer cells starve themselves to death for lack of adequate energy supplies.22

We can naturally activate AMPK in our bodies through several time-honored mechanisms. Calorie restriction lowers cellular energy stores and activates AMPK.23 Known to increase life span in virtually all species, calorie restriction has been shown to reduce cancer incidence and death in primate studies.24,25 And a recent study showed that gastric bypass surgery not only produced sustained weight loss, but also reduced cancer incidence by 42% in women patients (no effect was seen in men).6,26

Exercise is another strong natural activator of AMPK, and studies show that people with the highest levels of physical activity are protected against cancers of the lung and colon by as much as 30%.6,27,28

Exercise and weight loss are lifestyle changes that most of us need to make, while bariatric surgery and massive calorie restriction have more limited appeal and application as means of activating AMPK and lowering cancer risk.

Metformin, a natural product of the French lilac,29 is a safe, readily available, and inexpensive way to activate AMPK and starve cancer cells of their energy supplies.6,30,31 In doing so, metformin powerfully restores healthy regulation—both of metabolic factors and of those that regulate cell growth.

Let’s now examine how metformin halts incipient cancers by quelling abnormal cellular proliferation, one of the earliest steps in cancer development.

Metformin Combats Diabesity and Cancer
Metformin Combats Diabesity and Cancer
  • The anti-diabetic drug metformin was recently shown to slash risk of all cancers by 54% among 8,000 diabetics over a 10-year period.
  • Prognosis among those under study who developed cancer was also significantly improved, including cancers of the lung, colon, and breast.
  • Supportive epidemiological studies reveal that people taking metformin for glucose control have markedly reduced rates of cancer, despite the higher cancer risks imposed by diabetes and obesity.
  • Detailed molecular analyses are elucidating the mechanisms by which metformin prevents cancer.
  • Metformin works through a common mechanism to lower blood glucose and to reduce cancer risk, shedding new light on the intimate relationship between diabetes, obesity, and cancer.
  • Laboratory and clinical data now strongly suggest that metformin can prevent cancers of the colon, lung, and breast, even in non-diabetic individuals.
  • If you are concerned about lowering your cancer risk and improving your metabolic profile, ask your doctor about starting a metformin regimen at a dose of 250-500 mg twice a day.

Metformin’s Anti-Cancer Power Confirmed in Lab Studies

Healthy, normal people develop incipient cancer cells in their bodies daily; these cells are normally destroyed by a number of natural processes. When those processes break down, the cancer cells are free to proliferate and form a tumor. An ideal anti-cancer drug, then, would eliminate these altered, “precancerous” cells before they could replicate and become invasive and malignant.32

Even in their earliest stages, aggressive cancer cells are notoriously energy-hungry, burning calories at a frenetic rate as they grow out of control.33 For that reason, targeting cancer cell metabolism now stands at the forefront of cancer prevention research.34 With its potent ability to shut off the cellular energy pipeline by activating AMPK, metformin is showing its value in preventing or slowing a host of cancer types in laboratory studies.

The consequences of AMPK activation by metformin are numerous. Metformin, added to cultures of many different cancer cell types, blocks proliferation by “stalling” cells at one of several phases of the cell replication cycle, preventing them from reproducing.34-37 Metformin’s ability to starve cancer cells of energy also enhances the rate of cell death by the process known as apoptosis, one of the body’s natural means of cancer control.34,38

Perhaps the most detailed picture of metformin’s antiproliferative actions comes from a 2011 study in France.38 Researchers there added metformin to melanoma skin cancer cells in culture, and monitored the effects. At 24 hours, metformin had starved the cancer cells to the point that their replicative cell cycle was arrested. By 72 hours, the cells underwent autophagy, a mechanism whereby starving cells literally “eat themselves” in a desperate attempt to survive. And by 96 hours, the cancer cells began dying off en masse by apoptosis.

Several additional antiproliferative mechanisms have recently been demonstrated for metformin in addition to its effects on the AMPK energy-sensing pathway.35,39-42 That ability to act by multiple mechanisms is called pleiotropy. It is powerfully beneficial because it prevents development of resistance to any one pathway. Pleiotropy is seen much more commonly with natural products such as metformin than with mono-targeted pharmaceutical drugs.

The combined effect of all of metformin’s pleiotropic mechanisms is a marked reduction of tumor growth in lab animals implanted with human cancer cells.36,43 To date, metformin-induced antiproliferative effects have been demonstrated in cancers of the brain, lung, breast, ovary, prostate, and colon.35-38,44-47 And human studies are now showing important reductions in various tumor markers when metformin is provided to breast cancer patients prior to tumor surgery.48 Importantly, in breast cancer cells, metformin is most active against cancer strains that are resistant to standard chemotherapy drugs.46

Caution
Caution

Using metformin may increase the risk of lactic acidosis, a rare but potentially fatal buildup of lactic acid in the blood. Since congestive heart failure, kidney impairment, and liver problems increase the risk of lactic acidosis, individuals with these conditions are advised against using metformin. Individuals with type 1 diabetes should not take the drug. People who have recently suffered a heart attack or stroke and those who have recently undergone surgery or are severely dehydrated are more vulnerable to lactic acidosis.63-65 Consult with your doctor if any of these conditions applies to you or if you are pregnant, planning to become pregnant, or breastfeeding.

Lactic acidosis is a medical emergency. Its symptoms include muscle pain, difficulty breathing, sleepiness, feeling extremely weak or tired, and abdominal pain with nausea, vomiting, or diarrhea.63-65 If you believe you are suffering from lactic acidosis, seek medical attention immediately.

Metformin Prevents Cancers in Non-Diabetic Individuals

Perhaps the most exciting news to come out of the recent surge in interest in metformin is that the drug can prevent cancers from forming in animals and humans who are not diabetic. As a “mimicker” of a calorie-restricted state, that might be expected of metformin, given that calorie restriction is such a potent cancer-preventive strategy.33,49-51

Since 2008, a small explosion of studies has appeared demonstrating how effective metformin can be in this context, ultimately suggesting that it should be taken regularly by anyone who wants to reduce their risk of dying from cancer.

Research now demonstrates that metformin, provided orally to lab animals, prevents deadly colorectal cancers52 (the second leading cause of cancer deaths in the US, and an astonishingly preventable disease).53 Metformin suppresses intestinal polyp growth, a precursor of colorectal cancer, in mice predisposed to that disease.54 And, in a study of chemically induced colon cancer, metformin significantly reduced formation of so-called “aberrant crypt foci,” which in humans represent an early stage in cancer development.55

Those studies led to the first human study of metformin as a cancer preventive agent in non-diabetic people. Researchers studied 26 non-diabetic people with aberrant crypt foci that had been found on routine colonoscopy.56 They randomly assigned them to receive metformin 250 mg per day, or no treatment, and then performed repeat colonoscopy one month later. The metformin group had a significant decrease in the number of aberrant crypt foci, from nearly 9 per patient down to about 5 per patient, while control patients had no change. This represent a 55% reduction in this cancer precursor in patients taking low-dose metformin.

Chemoprevention studies now also demonstrate similar effects in other cancers. Mice supplemented with oral metformin, exposed to a potent tobacco carcinogen, developed 53% fewer lung cancers than did control animals.57 And when metformin was administered by injection, that protection rate rose to 72%.

Breast cancer prevention would represent a huge forward stride in extending human life span and reducing suffering. There’s encouraging data here as well. Mice given metformin in their drinking water for 13 days prior to injection with a powerful breast carcinogen had significantly delayed onset of tumor development.58 Several other studies have demonstrated that metformin-supplemented mice experience a reduction in proliferation of cancer-prone breast cells and inhibition of tumor growth.31

There is now a tremendous body of literature showing that metformin prevents cancer cells from proliferating, and moreover it prevents clinically relevant human cancers from developing, even in non-diabetic, non-obese individuals.59 As a result, one might expect to see large clinical trials of metformin in healthy older adults as a cancer chemopreventive agent.

Sadly, even though calls for such studies are gathering strength, to date no trial has been designed, let alone implemented.60-62 Given metformin’s impressive safety record over nearly 50 years of clinical use,43 there is simply no reason for sensible people to wait for an “official” medical establishment recommendation. People who are concerned about their growing risk of cancer should simply speak to their physicians now, and present them with a synopsis of the data, so that they can begin potentially lifesaving use of metformin today.

Summary

Summary

The anti-diabetic drug metformin was recently shown to slash risk of all cancers by 54% among 8,000 diabetics over a 10-year period while significantly improving prognosis among those who developed cancer, including cancers of the lung, colon, and breast.

Diabetes and obesity are twin risks for cancer development. Metformin offers powerful protection against cancer in those populations. Aggressive scientific research is revealing that metformin’s action, activating the cellular energy sensor AMPK, is the key to both its metabolic benefits and its cancer chemopreventive capabilities.

Both human and animal studies definitively confirm that metformin lowers cancer risk dramatically while also preventing new cancer formation, in both diabetic and non-diabetic individuals. Metformin’s 50-year safety record, coupled with its low cost and favorable side effect profile, provide an ironclad rationale for most aging humans to consider taking metformin.

If you have any questions on the scientific content of this article, please call a Life Extension® Health Advisor at 1-866-864-3027.
References
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Researchers develop more effective way to discover and test potential cancer drugs

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Posted 18 Nov 2011 — by James Street
Category Drug Testing, Drugs, Off-Label use

SAN FRANCISCO — Researchers have created a new phenotypic screening platform that better predicts success of drugs developed to prevent blood vessel tumor growth when moving out of the lab and onto actual tumors.

“This platform allows us to predict what’s going to happen in preclinical models,” said Enrique Zudaire, Ph.D., staff scientist in the radiation oncology branch of the National Cancer Institute, who presented the findings at the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics, held Nov. 12-16, 2011. “This not only shortens the amount of time that you would need to do screenings and drug discovery but also enhances dramatically the success you’re going to have in the next phases.”

Zudaire and colleagues developed a phenotypic, high-content, cell-specific fluorescence platform that examines the effectiveness of angiogenesis inhibitors, which shut down or impede tumor growth by hampering blood vessel formation and thus starve the tumor.

Past research has mainly focused on identifying single molecular targets for angiogenesis inhibitors. The new phenotypic platform evaluates how angiogenic inhibitors affect simultaneously entire cells and several steps of the angiogenesis process.

“If you do a screening for activity of a particular enzyme, that’s all you’re going to get: a drug that targets that specific enzyme activity. That tells you little about how the enzyme works in a complex organization,” said Zudaire. As a result, he explained, when many of these drugs advance to phase 2 clinical trials, they are either ineffective or result in side effects that are toxic to the patient.

Researchers validated the platform by screening the 1,970 small molecules that are part of the National Cancer Institute Developmental Therapeutics Program Diversity Set. Through the phenotypic platform, they identified more than 100 lead compounds that were then tested in preclinical models. All tested compounds showed antitumor activity, and some blocked tumor growth more effectively than current, FDA-approved antiangiogenic drugs.

This screening platform also ensures that researchers do not precondition the system to a known target. “We sometimes assume we know a lot about how these tumor systems work and what we should target,” said Zudaire.

The researchers proposed that most of the therapeutically relevant information in pathological systems rests on the complex interactions between the different components of the system rather than on the components themselves. Interrogating these systems in an unbiased manner will reveal not only single molecular targets but unknown interactions between them, which are relevant for the disease.

Ultimately, using this type of phenotypic platform can make drug development more efficient and cost-effective.

“If we improve the initial phases of drug discovery, we can decide where to invest time and money on drugs that are a lot more likely to work,” Zudaire said. “This study is proof of principle that the platform works. From here, we can design assays that are more complex and better able to describe what the in-vivo situation will be.”

Computational method rapidly discovers new uses for approved drugs

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Posted 10 Oct 2011 — by James Street
Category Combination Treatments, Drugs, Off-Label use

August 18, 2011 — 9:52am ET | By

Dust off those old drugs. A Stanford University group has developed a computational method for finding potential new uses for previously approved drugs. And two papers published Wednesday in the journal Science Translational Medicine suggest the potential promise of this approach.

The development comes as the NIH is pushing so-called drug repositioning, or finding new uses for drugs developed for other diseases. The agency, which provided funding for the studies, says repositioning strips away some of the big expenses of development and offers new, affordable ways to treat illnesses. With the support of repositioning advocates, the Stanford group’s technology has made progress in finding two repositioned drugs with some signs of efficacy in mouse models of inflammatory bowel disease (IBD) and lung cancer.

The group’s computational approach involves algorithms that are applied to such data sources as molecular profiles of diseases and drug information to predict novel uses for meds. In the IBD study, the group let its computational method loose on public gene-expression data and information on 164 small-molecule drugs. The system discovered that the anticonvulsant topiramate might treat IBD, and mouse experiments confirmed that hypothesis. The ulcer drug cimetidine, which the system identified as a potential lung cancer treatment, showed activity against the tumors in mice.

Obviously, there need to be further studies to prove whether the drugs work in humans. Yet what impressed in the Stanford group’s papers was the ability quickly analyze large volumes of data to develop hypotheses about new uses for compounds, Rochelle Long, of the National Institute of General Medical Sciences, told the Wall Street Journal.

Smelling a commercial opportunity, upstart NuMedii has formed to take the Stanford technology to the next level. Eric Schadt, a leader in using computational methods in drug research and the chief scientist at Pacific Biosciences ($PACB), is listed on NuMedii’s website as a scientific advisor to the start-up.

- read the Stanford release
- see the abstract on the IBD study
- here’s the abstract on the lung cancer research
- check out the WSJ‘s piece
- and NuMedii’s website

November 23, 2009 — 10:35am ET | By

The provider of a service that helps drugmakers consider drug repositioning options is going global. The service, which evaluates the impact of compounds on microRNA, provides information to developers on the application and toxicology of compounds in various disease areas and covers a selection of modes of action.

Scottish life sciences company Sistemic will set up shop in Boston. It will offer services for the development and application of novel drug discovery platforms based on the biology of small non-coding RNA.

Some in the sleepy investor community are willing to gamble on the repositioning idea, which represents a means of rescuing expensive development efforts that don’t yield marketable drugs. Privately held German biotech Kinaxo–which makes technology tools for drug mode-of-action analysis, cellular target profiling, drug repositioning, and biomarker identification–has just completed a financing round that saw the addition of two new funders.

Currently available tools include Invitrogen’s NCode Profiler data analysis software for microRNA profiling.

- read the Sistemic article
- here’s the Kinaxo announcement

July 3, 2007 — 12:01am ET

New York Times scribe Andrew Pollack takes a careful look at the current trend of making new drugs out of combinations of old therapies. Despite reporting one trial failure last week, CombinatoRx is out in the lead on this one. Researchers at the company are systematically running through the possible combinations of 2,000 generic drugs. But Pozen, Orexigen and other biotechs have combinatorial programs in place as well.

- read the article from The New York Times

Related Articles:
FDA buoys Pozen, accepts of amended response. Report
Orexigen Therapeutics files $86 million IPO. Report

 

AHFS Review Process for Off-label Oncology Uses

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Posted 19 Jun 2011 — by James Street
Category Drug Interactions, Drugs, Off-Label use

AHFS Drug Information Home

The mission of AHFS is to provide an evidence-based foundation for safe and effective drug therapy. A key component to this mission is the ongoing evaluation of evidence concerning offlabel uses of drugs. Section 1861 of the Social Security Act established AHFS DI as an official compendium for determining medically accepted indications of drugs and biologics used in anticancer chemotherapeutic regimens under Medicare Part B. AHFS DI meets the definition of a compendium as established in Section 414.930 of the Code of Federal Regulations (CFR) and has implemented enhancements to meet the desirable characteristics of compendia for use in determining medically accepted indications of drugs and biologics in anticancer therapy as recommended by the Centers for Medicare and Medicaid Services (CMS) Medicare Evidence Development and Coverage Advisory Committee (MedCAC). AHFS DI also has implemented policies and procedures to comply with the conflict of interest and transparency requirements for compendia as established by amended CFR Section 414.930(a); these requirements apply to determinations of medical acceptance in anticancer therapy made on or after January 1, 2010.

The following procedures, effective as of January 1, 2010, outline the process used by AHFS for determination of the medical acceptance of off-label uses for drugs and biologics in anticancer chemotherapeutic regimens under Medicare Part B.

The process for determination by AHFS is transparent and mitigates potential conflict of interest in order to preserve the compendium’s integrity and minimize bias. Strict firewall and conflict of interest polices are in place between AHFS staff and outside interests, to prevent any undue influence.

 

Selection of Off-label Oncology Uses for Consideration by the AHFS Oncology Expert Committee

Potential off-label oncology uses selected for consideration and review by the AHFS Oncology Expert Committee, for the purposes of determining medical acceptance, are identified by AHFS staff through either an internal process (i.e., ongoing literature review, advice of the Expert Committee) or an informal external request. AHFS employs a publicly transparent process for evaluating therapies as defined by CFR Section 4141.930(a) and that includes criteria used to evaluate the use, a listing of evidentiary materials reviewed by the compendium, and a listing of all individuals who participated substantively in the development, review, or disposition of the request. (See AHFS Conflict of Interest and Disclosure Policy.)

For the purposes of establishing medical acceptance, preference is given to clinical studies that have been published in a peer-reviewed journal and present results addressing the study objectives defined a priori. Clinical information from professional meetings, in the form of abstracts, posters, or presentations, may be considered under certain circumstances, especially if the information represents fully completed studies or is in response to a data safety monitoring board (DSMB) request. In addition, information from professional meetings may be considered for use in updating descriptive information for a trial summarized in an existing off-label determination (e.g., to reflect data from longer-term follow-up of study participants). Interim results typically are addressed only when they add importantly to the understanding of an existing off-label use (e.g., new information about potential toxicity, evidence about major changes in outcomes relative to previous findings) or a major clinical breakthrough seems likely. Both the quality of evidence and the clinical importance of the use, as reflected by the following criteria, are considered by AHFS staff when selecting an off-label use for review by the AHFS Oncology Expert Committee:

  • Clinical results from a well-designed and well-conducted phase 3 randomized trial comparing a novel regimen with a reasonable ‘standard of care’ (e.g., adequate sample size, full reporting of study end points)
  • Clinical results from a well-designed and well-conducted phase 2 trial in rare and refractory cancers for which there is no well-established regimen
  • Clinical results from a trial demonstrating a difference (improvement or worsening) in outcomes (responses, survival, quality of life, toxicity) compared with a reasonable standard of care
  • Clinical results from a trial reflecting the use of a regimen in the context of advances in the understanding of the biology of a disease (e.g., newly identified biomarker or surrogate end point)
  • Clinical results from a trial demonstrating a clinical difference (benefit or detriment) in a specific at-risk patient population (e.g., those with poor-risk cytogenetics, geriatric patients) or a subset of patients
  • A regimen with potential for improved quality of life (e.g., oral versus parenteral regimen)
  • A regimen/use described in a meta-analysis or an Agency for Healthcare Research and Quality (AHRQ)- or Cochrane-type evidence-based review

Once a potential off-label oncology use is identified, AHFS staff review and evaluate the relevant available evidence. After completion of the literature review, AHFS assigns an evidencebased rating for the specific off-label oncology use under consideration, using a composite score to rank the a) level of evidence of the supporting literature and b) the strength of the relevant end point as described in the ranking system of the National Cancer Institute-Physician’s Data Query (NCI PDQ) model.

Determination of Medical Acceptance

The relevant clinical information, based on the literature identified by AHFS staff, is incorporated into an evidence table and a narrative summary, which are provided to the AHFS Oncology Expert Committee for review.

AHFS Oncology Expert Committee members are asked to perform an independent review, complete a voting ballot, indicate their vote on the Level of Evidence rating, and provide a Grade of Recommendation and supporting comments using an evidence-based analysis of the available literature. (See AHFS Levels of Evidence Rating System and AHFS Grades of Recommendation.)

Publication of the Final Determination

A Final Determination Report for each off-label use reviewed by the AHFS Oncology Expert Committee is published on the AHFS website (www.ahfsdruginformation.com) and reflects the consensus vote of the members of the Committee. The following information is included in the Final Determination:

  • Criteria used to select the off-label use for review
  • Name of the drug or drug combination
  • Off-label use, to include specific patient population and disease information
  • Strength of Evidence, using composite score of strength of supporting literature and strength of end point
  • Grade of Recommendation
  • Narrative summary of the off-label use, including a description of the regimen, to facilitate consistent interpretation of the off-label recommendation
  • Listing of references used as part of the off-label review
  • Voting records
  • Comments provided by AHFS Oncology Expert Committee members
  • Listing of all individuals who substantively participated in the development, review, or disposition of the determination
  • A statement summarizing the management of recognized conflicts of interest for individuals who participated substantively in the determination process
  • AHFS publication date

A comprehensive review of the Final Determinations is conducted periodically, and relevant information (e.g., Level of Evidence and/or Recommendations) contained in the Final Determination is updated as needed.

Records pertaining to the publication of a Final Determination made on or after January 1, 2010 are maintained and available for not less than 5 years in accordance with CMS regulations. Such records will remain and be accessible on the AHFS website for a period of not less than 3 years, after which retention of the relevant information will be maintained for an additional 2 years by ASHP, thereby enabling public access to the material upon request.