The Costs of Clinical Trials and Drug Development

A recent report published in Pharmalot  shows that the cost of conducting clinical trials has risen to staggering figures.  Across all therapeutic areas, the average cost per patient in phase 1 trials rose from $15,023 in 2008 to 21,882 in 2011.  For phase 2 trials, the costs rose from 21,009 to $36,070 and in phase 3b trials, the costs increased from $25,707 to $47,095. If one adds the R&D costs to these, then one should not be surprised than billion dollar estimates have been proposed.  Whether costs are really this high is controversial and the debate continues.

Current estimates place the costs of developing new drugs somewhere between $1.0 billion to $1.5 billion.  A report by Pharmaceutical Research and Manufacturers of America (PhRMA) estimated that the costs for drug development were  $1.38 billion in 2005. This figure was of course much higher than the previously reported and often quoted cost of $802 million (see DiMasi et al].   The most recent estimates come from a report commissioned by an independent UK research organization called the Office of Health Economics and summarized recently in The Burrill Report .  Despite the staggering costs, the success rate for bringing a new drug from early human trials to market has declined to 1 in 10.  The issue of increasing costs of clinical trials and the causes of this increase has been studied in a recent report written by Avik S. A. Roy, a Senior Fellow, Manhattan Institute for Policy Research, entitled ” Stifling New Cures: The True Cost of Lengthy Clinical Drug Trials”.  The report can be accessed as a pdf document at the Manhattan Institute website.

The cost estimates vary depending on the methodology used, the type of therapy and the company developing the drug.  Christopher Adams and Van Brantner from the Bureau of Economics, Federal Trade Commission, used estimates similar to those of DiMasi et al. but a publicly available database to reach their cost estimates [see here].   They concluded that [estimates vary from around $500 million to more than $2 billion, depending on the therapy or the developing firm].  Recent reports are critical of the costs calculated by PhRMA and the pharmaceutical industry as a whole.  They suggest that such figures may have been inflated and that the real cost of drug development may be much lower.  This issue was recently addressed in an editorial written by Michael Hiltzik in Aug 3, 2011 in Los Angeles Times.  The editorial is based on the findings of a recent article written by Donald Light and Rebecca Warburton in BioSocieties.

© Copyright M. Loghman-Adham, MD

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OMONTYS® (peginesatide) recalled due to fatal allergic reactions

On February 23, 2013, Affymax and Takeda announced a voluntary nationwide recall of all lots of Omontys (peginesatide), a peptide mimetic erythropoiesis stimulating agent (ESA), which was approved on March 27, 2012 by the FDA for the treatment of anemia due to chronic kidney disease in adult patients on dialysis (see here and here).  Peginesatide has the advantage over currently available ESAs on the US market that it can be administered once monthly by either intravenous or subcutaneous routes.  Additional information is available on the FDA website.

Post-marketed surveillance has shown hypersensitivity reactions in 0.2% of subjects, with serious-life threatening reactions occurring in one-third.  In a joint News Release, the Companies report that, since launch, more than 25,000 patients have received peginesatide and fatal reactions have been reported in approximately 0.02% .  A Dear Healthcare Provider letter has been posted on the Omontys website informing prescribers to cease using the drug.

The prescribing information for Omontys does carry a black box, which  is now required for all ESAs.  There were no anaphylactic reactions reported in the label, which restricts itself to those AEs with a frequency of ≤ 10%.  It does indicate the risk of immunogenicity and production of neutralizing antibodies.  Below is an excerpt from the label:

[Of the 2357 patients tested, 29 (1.2%) had detectable levels of peginesatide-specific binding antibodies. There was a higher incidence of peginesatide-specific binding antibodies in patients dosed subcutaneously (1.9%) as compared to those dosed intravenously (0.7%). Peginesatide neutralizing antibodies were detected in vitro using a cell-based functional assay in 21 of these patients (0.9%).]

Editor’s Comments: The occurrence of fatal anaphylactic reactions with the reported frequency of 0.02% or 1 in 5000 patients dosed with peginesatide has very negative consequences.  According to the Affymax and Takeda, serious, but non fatal hypersensitivity reactions were observed at a frequency of 0.2% (2 in 1000).  Such reactions were not observed during phase 2 and phase 3 trials of peginasetide where 1066 patients received the drug.  It is for this reason that post-marketing surveillance and REMS are being required by the FDA at the time of approval for many new drugs.  Whether serious anaphylactic reactions were a consequence of the known immunogenicity of the drug or due to increased immunogenicity of specific batches is not clear at this time.  We also do not know if these subjects received the drug by the subcutaneous route, known to be more immunogenic than the intravenous route.

© Copyright M. Loghman-Adham, MD

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Targeted therapy with folate-conjugated rapamycin, a promising treatment for PKD

Autosomal dominant polycystic kidney disease(ADPKD) is a common genetic kidney disease caused by mutations in either PKD1 or PKD2 genes, resulting in the presence of multiple cysts that increase in size and lead to a number of complications, including early-onset hypertension, hematuria, pain, infection, and slowly progressive chronic kidney disease that leads to end-stage renal disease by the 6th decade of life.

Dr Thomas Weimb’s group at UC Santa Barbara had shown that mTOR pathway is involved in polycystic kidney disease and that it’s inhibition reverses cyst formation in two different mice model of polycystic kidney disease, namely the Tg737orpk/orpk;TgRsq and the bpk/bpk mice (see Shilingford et al).  This discovery led to two recently completed clinical trials of mTOR inhibitors, already approved as immunosuppressive agents in organ transplantation. These studies were published in the August 26, 2010 issue of New England Journal of Medicine.

The trial by Serra et al. included 100 ADPKD patients with relatively preserved renal function, treated with sirolimus or placebo for 18 months. Kidney volume and GFR were measuerd over time.  The authors found no difference in kidney volume change between the sirolimus and the placebo-treated subjects and no difference in GFR between the two groups.  In another study by Walz et al. published in the same issue of New England Journal of Medicine, 433 ADPKD patients were randomly assigned to receive everolimus or placebo for 24 months. In this study, everolimus resulted in a statistically non-significant slowing of the kidney volume growth compared to placebo, but no difference in GFR was observed between the two groups.  The everolimus group experienced a significantly higher rate of adverse events contributing in a higher rate of discontinuation in the everolimus group.

The issues related to the use mTOR Inhibitors in ADPKD and some of the reasons for the failure of the studies by Waltz et al. and Serra et al. have been very nicely summarized in the commentary written by Terry Watnick and Gergory Germino that accompanied the publications of these two studies in same issue of  the New England Journal of Medicine.  A major issue with mTOR inhibitors is their toxicity at high doses, making it impossible to reach therapeutic drug levels within the kidney that have been shown in rodent models to slow the growth of cysts. To be effective, these agents must be targeted to be delivered at relatively high concentrations to the cysts within  the kidney.

In a recent study published in the September 28, 2012 issue of the American Society of Nephrology, Jonathan Shillingford et al.  used a folate-conjugated form of rapamycin (FC-rapa) to target renal cells.  They first showed that normal tubules and cysts-lining epithelial cells from human patients and two murine models of PKD express folate receptors.  Treatment of the mouse PKD models with FC-rapa reduced cyst proliferation and preserved renal function. The technology to produce folate-conjugated drugs for targeted therapy comes from Endocyte, a biotech company headquartered in Lafayette Indiana.  Endocyte is developing small molecule drug conjugates for treatment of cancer, autoimmune diseases and PKD, using the folate receptor targeting technology.

A summary of this study and the collaboration with Endocyte can be found on a news release from the University of California Santa Barbara, where Dr Weimb’s laboratory is located.

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Trials and tribulations in kidney disease

On November 3, 2012 at the recent meeting of the American Society of Nephrology-Kidney Week  in San Diego, the results of three important clinical trials in nephrology were presented during  a special session on High Impact Clinical Studies.

The first report presented by Dr Hans-Henrik Parving , University of Copenhagen was the result of the ALITITUDE Trial.  This study was undertaken to determine whether the addition of aliskiren, a direct renin inhibitor to either an ACE inhibitor or an angiotensin receptor blocker (ARB) in patients with type 2 diabetes and chronic kidney disease (CKD) would lead to a reduction in cardiovascular and renal events in this high-risk population.  We reported that on December 20, 2011 the  ALTITUDE Trial was discontinued on recommendation of the Data and Safety Monitoring Board [KDDD].   Therefore, the report on the final data was anxiously awaited.  It was confirmed that, in patients with type 2 diabetes and CKD who are at  high risk of cardiovascular and renal events,  the addition of aliskiren to the standard therapy with RAS blockade does not provide additional benefit and may be harmful due to the increased risk of hyperkalemia.  The results of the trial were simultaneously published in the New England Journal of Medicine.  A summary of the trial and commentary can also be found at Heartwire.

The second report presented by Dr Vicente Torres, Mayo Clinic, Minnesota was the result of a phase 3 trial of tolvaptan, a vasopressin V2 receptor antagonist in patients with autosomal dominant polycystic kidney diseases (ADPKD).  Tolvaptan is already approved and marketed by Otsuka under the brand name Samsca for the treatment of clinically significant hypervolemic and euvolemic hyponatremia.

Previous work in animal models of ADPKD had shown that blockade of vasopressin V2 receptors slows cyst growth by down-regulating cAMP signaling (see Devuyst et al).  The TEMPO 3:4 trial was a pivotal phase 3 multicenter trial including 1445 adult patients with ADPKD and relatively preserved GFR and a total kidney volume (TKV) of 750 ml or more.  Patients with larger TKV have been shown to  have more rapid increase in kidney size, and likely more rapid progression of disease.  Over the 3 years treatment period, the decrease in TKV was lower in the tolvaptan-treated patients compared to placebo (2.8% vs 5.5% per year).  There was also a lower incidence of kidney pain and slower decline in kidney function, as measured by the reciprocal of serum creatinine, in the tolvaptan group.  Adverse events leading to discontinuation were higher in the tolvaptan group.   Not surprisingly, thirst, polyuria and nocturia were reported more frequently in the tolvaptan group with a frequency more than double that of placebo group.  The next step will be the submission of a New Drug Application (NDA) to the FDA.  Otsuka had previously obtained fast track designation for tolvaptan in ADPKD, which will allow a faster review and approval  process.   Should tolvaptan be approved for treatment of ADPKD, it will be the first drug specifically developed for this indication.  The results of TEMPO 3:4 trial were simultaneously published in New England Journal of Medicine as well.  A summary of the results can also be found at the eAJKD blog.

The third report presented by Dr Glenn Chertow, Stanford University, California was the result of a phase 4 trial of the calcimimetic agent, cinacalcet (Sensipar, Amgen) called Evaluation of Cinacalcet Therapy to Lower Cardiovascular Events (EVOLVE) Trial.  The rationale to conduct this trial was based on reports from observational studies of patients receiving dialysis treatment that showed elevated serum phosphorus, calcium, parathyroid hormone and alkaline phosphatase were associated with increased risk of cardiovascular events and death (see here and here).   The results of the EVOLVE Trial were also published in New England Journal of Medicine.  The study enrolled 3883 hemodialysis patients with moderate hyperparathyroidism (median iPTH 693 pg/mL) to receive either cinacalcet or placebo.  The patients were followed for up to 64 months and the median treatment duration was 21.2 months.  The study results showed that cinacalcet did not significantly reduce the risk of death or major cardiovascular events in this high risk patient group.  A summary of the results of this trial is also available at Heartwire.

Commentary:  well designed randomized controlled trials (RCT) are considered  the gold standard to evaluate the effect of a therapeutic intervention.  Often epidemiological or observational studies may suggest a link between an abnormal laboratory test (e.g. phosphorus) or a biomarker (e.g. CRP)  and a clinical outcome such as mortality.  However, this does not mean that correcting the laboratory abnormality with a therapeutic intervention will necessarily alter the outcome.  Only a well-conducted RCT will be able to provide a definitive answer.  In this respect, we must congratulate the sponsors and the investigators of ALTITUDE and  EVOLVE Trials for undertaking these well conducted studies without which these questions would not have been answered.  We can now focus our attention on testing other hypotheses related to the causes of increased cardiovascular morbidity and mortality among CKD patients, especially those receiving chronic dialysis.

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Phase 3 Clinical Trial of CKD Drug Bardoxolone Halted on Safety Concerns

Reata Pharmaceuticals announced yesterday (Oct 18, 2012) that it has decided to terminate the phase 3 clinical trial of Bardoxolone methyl [BEACON] for treatment of patients with stage 4 kidney disease and type 2 diabetes.  Abbott is co-developing Bardoxolone and has  the rights to develop this drug outside the US market.  Bardoxolone has generated a lot of interest within the nephrology community, since there have been no new safe and effective treatments to slow or reverse the progression of CKD other than ACE inhibitors or angiotensin receptor blockers.  I had previously reported on the results of the phase 2 dose ranging trial of Bardoxolone that had shown some safety concerns including muscle spasms, hyperkalemia and hypomagnesemia.  But the new finding of increased mortality in the active treatment arm were unexpected.

The company announcement can be found here [Reata-Bardoxolone] and below:

Reata, in consultation with the BEACON Steering Committee, has decided to terminate the Phase 3 BEACON trial of bardoxolone methyl in patients with stage 4 chronic kidney disease and type 2 diabetes.  This decision was made based upon a recommendation of the Independent Data Monitoring Committee (IDMC) to stop the trial “for safety concerns due to excess serious adverse events and mortality in the bardoxolone methyl arm.”

Clinical trial sites have been notified, and patient participants are being instructed to stop taking study drug and return to the clinic for a final visit.  In addition, Reata and Abbott have notified the FDA and other regulatory agencies of the decision to stop the clinical trial and all ongoing clinical trials with bardoxolone methyl in CKD.

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Calcium-Free Phosphate Binders – Review

This article was originally published in abbreviated form at an Spanish on-line journal [].  The attached pdf link is the full version, not published previously.  The article summarizes the issues related to phosphate retention, excess calcium absorption due to the use of calcium-containing phosphate binders and some of the data related to adverse cardiovascular consequences related to the exclusive use of such binders.  This is followed by a discussion of calcium-free phosphate binders such as sevelamer and lanthanum carbonate.  For more up-to-date information, the reader is encouraged to read some of the excellent recent reviews such as the one by Malindretos, published this month in Expert Opinion in Pharmacotherapy.

Phosphate binders-Updated 10-12

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Nephrotoxicity During Drug Development

A new review of this subject entitled Detection and Management of Nephrotoxicity during Drug Development has been recently published in Expert Opinion on Drug Safety. The article has been available ahead of print on-line since May 22, 2012.  The authors are members of Renal Safety Expert Group at Roche pharmaceutical company and have many years of combined experience in nephrology, drug development and drug safety.  Previous reviews of the subject have focused on acute kidney injury (AKI) and do not distinguish between different causes of AKI such as ischemia, sepsis or nephrotoxins.  The article by Loghman-Adham et al. is is one of the first articles that specifically addresses drug-induced nephrotoxicity (DIN) and provides practical guidance for risk mitigation and early detection of DIN during all phases of drug development. The application of biomarkers of nephrotxicity is discussed and there are a number of useful tables and figures that provide practical information on how to diagnose and manage DIN.  For complete disclosure, I am one of the authors of this paper.  Below is a link to the journal and the abstract of the article.

Reviewed  by Mahmoud Loghman-Adham, MD

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ALTITUTE trial of aliskiren on top of ACE or ARB discontinued on DSMB recommendation

Dec 20, 2011 Shelley Wood from heartwire
Basel, Switzerland – An increase in adverse events and no apparent benefits among patients randomized to aliskiren (Rasilez/Tekturna, Novartis) in the ALTITUDE trial has prompted the data safety and monitoring board (DSMB) for the study to recommend its termination, the sponsor announced today [Novartis press release here].

ALTITUDE was studying aliskiren on top of ACE-inhibitor or angiotensin-receptor-blocker (ARB) therapy in patients with type 2 diabetes and renal impairment compared with a placebo add-on.

In making its recommendation, the DSMB noted that the active-treatment group experienced an increased incidence of nonfatal stroke, renal complications, hyperkalemia, and hypotension over 18 to 24 months of follow-up. The committee concluded that patients were unlikely to benefit from aliskiren on top of standard antihypertensive therapy.

“Novartis is in ongoing discussions with health authorities worldwide about the implications of the findings from ALTITUDE for patients,” a press release reads. “As a precautionary measure, Novartis will cease promotion of Rasilez/Tekturna-based products for use in combination with an ACE inhibitor or ARB.”

The company is also checking in with the DSMBs of other clinical studies studying aliskiren alone or in combination.

ALTITUDE investigators are being told to remove aliskiren from their patients’ treatment regimen and review their current blood-pressure medications; patients in ALTITUDE are advised to contact their doctors.

Earlier this year, positive results of the ACCELERATE trial looking at aliskiren in combination with a calcium-channel blocker were published in the Lancet. Last year the FDA approved both a dual- and triple- combination drug including aliskiren, but neither drug included an ACE inhibitor or ARB.

Original source: Heartwire

Novartis Press Release: ALTITUDE press release

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The FNIH Biomarkers Consortium Launches Project to Improve Diagnosis of Kidney Injury

Bethesda, MD (November 1, 2011) – The Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium announced today the launch of a two-year clinical study aiming to advance the acceptance of new biomarkers designed to detect drug-induced kidney injury in clinical trials. The study is being conducted in collaboration with the Predictive Safety Testing Consortium (PSTC), a public-private partnership founded by the Arizona-based non-profit Critical Path Institute (C-Path).

The potential toxic effect of some medications on the kidney – or drug-induced nephrotoxicity -can be a serious problem for drug developers. The current standard biomarkers used to detect acute kidney injury are not sensitive enough and can produce false positive results; sometimes forcing researchers to abandon otherwise promising drug candidates. The FNIH Biomarkers Consortium Kidney Safety project is designed to test new biomarkers that are more sensitive, and will establish better criteria for when kidney safety concerns should halt further testing of a drug in humans.

“Patient safety is and must be our primary concern as we develop potential new medicines,” explained Gary Herman, M.D., Vice President, Early Stage Development at Merck Research Laboratories. “The FNIH Biomarker Consortium Kidney Safety project is critical to help identify biomarkers that improve the process of developing effective medicines that are safe to test and use with patients.”

The clinical studies will be conducted at four major U.S. medical research centers: the University of Southern California, the University of Minnesota, the Brigham and Women’s Hospital/Dana Farber Cancer Institute and the MD Anderson Cancer Center. Blood and urine samples will be collected from patients undergoing treatment with two different drugs known to cause injuries to the kidney tubule; cisplatin, a common type of chemotherapy drug taken by patients with head and neck cancer, and aminoglycosides, a common type of antibiotic drug taken by patients with cystic fibrosis.

The project will enable the continued development of potentially valuable compounds across a number of therapeutic areas, such as cancer, cystic fibrosis and diabetes. The data generated from this project is aimed to advance regulatory acceptance of new biomarkers appropriate for monitoring kidney safety in the clinic. Importantly, this data will improve clinical diagnoses of drug induced kidney injury during drug development and patient therapy.

“We need better ways of predicting potential kidney injury from new therapies early on in the development process,” said Janet Woodcock, M.D., Director of the Center for Drug Evaluation Research at the U.S. Food and Drug Administration. “The Biomarkers Consortium project represents a powerful collaborative approach to qualifying the biomarkers needed to accomplish this.”

The studies, managed by the FNIH Biomarkers Consortium, will build significantly on previous work to qualify kidney safety markers for use in animal studies conducted by the PSTC. The PSTC and C-Path are also providing healthy volunteer data, database, and biorepository services to support the Biomarkers Consortium effort. The project, led by Frank Sistare, PhD, of Merck Research Laboratories, will also include participation of a diverse group of experts from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at the National Institutes of Health (NIH), the Food and Drug Administration (FDA), several pharmaceutical companies, and academic organizations. Participating and funding organizations include Amgen, AstraZeneca, C-Path, Eli Lilly & Company, Johnson & Johnson, Merck Research Laboratories, and Pfizer.

For more information about this project, please visit or

About the Foundation for the NIH

Established by the United States Congress to support the mission of the NIH-improving health through scientific discovery in the search for cures-the Foundation for the NIH is a leader in identifying and addressing complex scientific and health issues. The Foundation is a non-profit, 501(c)(3) charitable organization that raises private-sector funds for a broad portfolio of unique programs that complement and enhance NIH priorities and activities. For additional information about the Foundation for the NIH, please visit

About the Biomarkers Consortium

The Biomarkers Consortium is a public-private biomedical research partnership managed by the Foundation for the National Institutes of Health (FNIH) that endeavors to develop, validate, and/or qualify biological markers (biomarkers) to speed the development of medicines and therapies for detection, prevention, diagnosis and treatment of disease and improve patient care. For additional information about the Biomarkers Consortium, please visit

Reported on November 9, 2011 by eteichert @
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STAT3 as a possible new drug target for polycystic kidney disease

Two discoveries at UC Santa Barbara point to potential new drug therapies for patients with kidney disease. The findings are published in this week’s issue of the Proceedings of the National Academy of Sciences.
Over 600,000 people in the U.S., and 12 million worldwide, are affected by the inherited kidney disease known as autosomal dominant polycystic kidney disease, or ADPKD. The disease is characterized by the proliferation of cysts that eventually debilitate the kidneys, causing kidney failure in half of all patients by the time they reach age 50.
Currently, no treatment exists to prevent or slow cyst formation, and most ADPKD patients require kidney transplants or lifelong dialysis for survival, explained Thomas Weimbs, director of the laboratory where the discoveries were made. Weimbs is an associate professor in the Department of Molecular, Cellular and Developmental Biology and the Neuroscience Research Institute at UCSB.
First, Weimbs and his research team discovered a molecular mechanism that sheds light on the disease. The mechanism concerns polycystin-1, a protein that is mutated in ADPKD patients. The team discovered how this protein regulates a well-known transcription factor called STAT3. Transcription factors transcribe information from DNA to RNA, from specific genes. Second, the team discovered that STAT3 is strongly, and aberrantly, activated in polycystic kidneys.
“The clinical significance of these discoveries lies in the fact that STAT3 is also known to be aberrantly activated in many forms of cancer and is considered an important drug target for cancer therapy,” said Weimbs. “Numerous STAT3 inhibitors are currently being developed and tested, and several experimental drugs are already available. Our results suggest that STAT3 activation is a driving force for the cyst growth that leads to polycystic kidneys in ADPKD. Therefore, STAT3 may be a highly promising drug target for the treatment of ADPKD.”
Weimbs explained further that STAT3 is a signaling molecule that is activated in response to many different growth factors binding to specific receptors on the surface of kidney cells. In response to these growth factors hitting the cell, STAT3 is activated. That causes STAT3 to turn on the expression of certain genes. This activity causes the cells to proliferate, as they do in cancer.
“In polycystic kidney disease, we have strong proliferation, but it is similar to having benign tumors — where the tumor stays in place,” said Weimbs. “The cysts keep growing, but they do not metastasize or invade other tissues as do cancerous tumors. Polycystic kidneys are full of small, benign tumors or cysts. This is still very destructive, because eventually the disease will destroy the kidney.” The research team is currently testing STAT3 as a drug target in mice with ADPKD.
The National Institutes of Health funded the research.

Source: ScienceDaily (Apr. 26, 2011)
The original article can be found at PNAS:

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