Posts Tagged ‘FDA’

Does the FDA Refer to Disease-State Models to Determine Safety?

Posted by CorDynamics on April 22nd, 2015

The answer is: sometimes.

FDA Orphan Drugs Rare Diseases Cholesterol

A few months ago I attended an excellent Safety Pharmacology Society webinar (Nov 2014, “Cardiac Safety Testing Models”) where the non-clinical examination of cardiac contractility was discussed.

Dr. Philip Gatti, from the US FDA, concluded that compounds with putative inotropic effects should undergo “better utilization of in vitro systems (Langendorff or wedge preps) or use of animal models of heart failure which would enhance sensitivity to such drug effects.

Our labs have interrogated the cardiovascular effects of test articles in a variety of underlying pathophysiological states, including subjects with hypertension to those with impaired respiratory capacity.

One of the more frequent drug safety conditions we are asked to model is the compromised or failing heart. Many project teams need to know if their compounds affect left ventricular hemodynamics in the presence of pre-existing cardiac dysfunction. Sometimes these properties may not exist in the normal subject. However, they may be present in the target population.

We have conducted these studies using multiple models, including the post-infarcted heart, hypertrophy following hemodynamic overload (such as transverse aortic constriction), and tachypaced-induced cardiomyopathy.

Similar questions are usually asked:

  • Is it appropriate to examine drug safety in animals with ‘disease-state’?
  • Is this a current regulatory expectation?
  • Is there a differential effect compared to ‘normal’ animals?

Using these approaches, we have uncovered substantive areas of concern while also mitigating issues that previously appeared insurmountable.

We know there is an important role for using the ‘disease-state’ subject in cardiovascular safety pharmacology assessments.

While most preclinical studies will continue to use normal animals for risk assessment, the inclusion of disease models where appropriate can help unmask notable toxicities that may only occur in the target patient population.

Filed under: Drug Safety Services, Heart Failure, Hemodynamics, Langendorff Heart | No Comments

Weight Loss Drugs Losing Traction with FDA and Docs?

Posted by CorDynamics on June 20th, 2014

Developing weight-loss drugs to help the estimated 35% of Americans struggling with obesity should be an easy gain for the biotech and pharmaceutical industry. As of late, it seems to be a losing proposition—for a variety of reasons.

Weight Loss Drugs Losing Traction with FDA and Docs?

FDA Extra Cautious with Safety and Marketing Regulations

Cardiovascular side effects are at the heart of the FDAs concern. The simple fact is that many biological pathways involved in appetite control are also shared with the cardiovascular system.

A generation ago, doctors were prescribing amphetamine-like stimulants, which were appetite suppressants, but also had very unfavorable cardiovascular side effects. In the 1990s the combination of fenfluramine and phentermine (fen-phen) resulted in appetite suppression as well but caused a pathological change in both cardiac valves and pulmonary arterial function.

This tumultuous history has made worldwide regulators particularly sensitive to cardiovascular safety in this therapeutic area. Case in point and as reported in FierceBiotech last week, Orexigen (OREX) had to wait three long years to take a second shot at an approval for its weight drug NB32, earlier called Contrave. Now the company has to wait another three months for an FDA marketing decision as they talk through a regulatory requirement on tracking cardiovascular outcomes among people taking the therapy.

Prescriptions Thin from Physicians

Doctors have not been prescribing weight-loss medications as often as was expected.  Previous safety concerns combined with marginal reported benefits from patients has made physicians think twice before suggesting the medications.

According to Bloomberg, the average weight loss was only 4 percent to 8 percent above what patients taking placebos demonstrated. While this is medically important, it may not be enough to offset side effects as headaches or upset stomach. Also some insurers are reluctant to cover co-pays for drugs.

It’s an interesting caveat. As drug developers we focus so much on FDA approvals, we have to remember the approval of doctors and patients is important as well.

Filed under: Drug Safety Services | No Comments

The FDA, Avandia and Cardiovascular Safety: The Sequel

Posted by CorDynamics on June 06th, 2013

by Dr. Michael Gralinski, CorDynamics CEO

FDA UPDATE: WASHINGTON (AP) 6/6/13– Federal health experts are recommending changes to safety restrictions on former blockbuster diabetes pill Avandia, in light of a new analysis suggesting that the drug may not increase the risk of heart attack as much as previously thought.

A majority on a Food and Drug Administration advisory panel voted Thursday to modify or remove measures that currently limit patient access to GlaxoSmithKline’s Avandia. Among those requirements, patients must sign a waiver before getting a prescription that they understand the drug’s risks.

Of the panel’s 26 experts, 13 voted to modify safety restrictions on Avandia while seven voted to remove them entirely. Five panelists voted to keep the measures in place without any changes, while one panelist voted to withdraw Avandia completely.

The vote is a recommendation to the FDA and is not binding.


The first week in June, an advisory panel of the FDA is meeting to conduct an independent ‘re-adjudication’ of a cardiovascular outcomes trial conducted in support of Avandia (rosiglitazone).

Just a few days ago, the FDA posted a 500+ page briefing document on its website.

The document, officially titled “Re-adjudication of the Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes Trial (RECORD)”, generally concludes that Avandia may in fact not be associated with increased cardiovascular risk and mortality.

The drug has been saddled with this cardiovascular question since a 2007 study from The New England Journal of Medicine showed a 43% increase in risk of myocardial infarction with patients on Avandia.

Sifting through the tables and charts, it became clear that this story has numerous twists and turns. Not often do the ups and downs of drug development, especially in a lucrative therapeutic area such as diabetes, get laid bare in the public eye.

Fascinating to this whole story are the struggles, accusations and defenses from the parties involved on all sides..…litigation, conflict of interest, misconduct, malfeasance, ‘whitewash’ advisory panels—much of which reads much like a intrigue novel. The culprit: cardiovascular safety.

Situations involving cardiovascular safety can be complex, requiring the right expertise to help sort the issues. It will be interesting to see the recommendations of this weeks’ expert advisory panel – and the decision of the FDA.


Filed under: Drug Safety Services, Preclinical Consulting Services | No Comments

Cracking the Case on Sudden Cardiac Death and Domperidone

Posted by CorDynamics on April 18th, 2013

by Liomar Neves, Senior Scientist

Recently, the Journal of Cardiovascular Pharmacology published an original article investigating sudden cardiac death and QT interval prolongation associated with domperidone that caught the attention of our CorDynamics team.

The Report

Domperidone is a dopamine receptor antagonist not approved by FDA for sale in the US market, but is widely used in more than 100 countries. Its purported benefits are as a gastrointestinal prokinetic agent, an anti-nausea and vomiting therapeutic and more recently it has been used to promote lactation.

However, the compound has been associated with disturbances in ventricular electrophysiology. These include increases in QT interval and cardiac rhythm disturbances.

In this recent preclinical study, the authors confirm that domperidone prolongs action potential duration and suggests that the IC50 for blocking the hERG channel IKr may be lower than previously reported.

New Evidence

The study also involved the use of prolonged domperidone exposure times, longer cycle lengths to examine reverse-use dependence, and use of rabbit hearts that are naturally heightened for sensitivity to IKr antagonism.

  • Evidence demonstrated domperidone to have a high affinity to IKr and low safety margin, thus increasing risk of drug-induced long QT syndrome and potential proarrhythmogenesis.
  • Additionally, the report brings attention to the limited benefits of domperidone for gastrointestinal disturbances and highlights the risk of using a low safety margin drug for a non-threatening target such as promotion of lactation.

The authors concluded the report by urging other regulatory agencies to take the FDA’s approach and ban domperidone’s use.

Filed under: Cardiac Ion Channels, Drug Safety Services, Electrophysiology, Langendorff Heart | No Comments

FDA Welcomes New Class of Diabetes Drugs

Posted by CorDynamics on April 03rd, 2013

Invokana (canagliflozin) has been approved by the FDA for patients with Type II diabetes—with two cardiovascular caveats.

  1. Leading up to approval, FDA reviewers highlighted the increased risk of cardiovascular problems to patients on the therapy as it lowered blood sugar but raised cholesterol in clinical trials.
  2. A complete cardiovascular outcomes trial must be conducted.

Ivonkana is at the head of the new class of SGLT2 inhibitors.

These inhibitors block a protein associated with the reabsorption of glucose in kidneys to help diabetics clear blood sugars more efficiently.

“Invokana is the first diabetes treatment approved in a new class of drugs known as sodium-glucose co-transporter 2 (SGLT2) inhibitors,” said Mary Parks, M.D., director of the Division of Metabolism and Endocrinology Products in the FDA’s Center for Drug Evaluation and Research. “We continue to advance innovation with the approval of new drug classes that provide additional treatment options for chronic conditions that impact public health.”

In a statement regarding the approval of Invokana, the FDA is requesting five postmarketing studies for Invokana: a cardiovascular outcomes trial; an enhanced pharmacovigilance program to monitor for malignancies, serious cases of pancreatitis, severe hypersensitivity reactions, photosensitivity reactions, liver abnormalities, and adverse pregnancy outcomes; a bone safety study; and two pediatric studies under the Pediatric Research Equity Act (PREA), including a pharmacokinetic and pharmacodynamic study and a safety and efficacy study.

Filed under: Drug Safety Services | No Comments

FDA Warns Azithromycin May Prolong QT Interval

Posted by CorDynamics on March 19th, 2013

Azithromycin_QTINterval_Warning_FDAIt’s been almost a week since our return from the 2013 Society of Toxicology meeting in San Antonio. While we try to keep up with things outside the trade show, it’s hard to do.

However, one news item caught my eye during the week. In fact, it was nearly impossible to miss as the lead or top level item on all the news channels.

The FDA warned the public that the antibiotic azithromycin could cause abnormal changes in the electrical activity of the heart that may lead to a potentially fatal irregular heart rhythm.

In a nutshell – QT interval prolongation.

The revised label has the most robust description yet of the drug’s ability to prolong QT interval in certain subsets of patients. Which got me thinking…

So many people have taken azithromycin over the years with great success. It works effectively for taking care of common respiratory infections. Azithromycin is literally a lifesaver in developing and yet-to-develop areas for conditions such as river blindness and community related infections where compliance can be nominal.

How could the industry have missed the QT interval prolongation in azithromycin?

The answer is actually straightforward.

First, azithromycin was approved on a wide basis in 1991. This was a number of years before stringent screening for safety pharmacology effects were in place.

Second, the adverse effects appear to limited to a small subset of patients – likely related to the vulnerable substrate hypothesis for proarrhythmogenesis. But when you actually take a close look at the preclinical data – the effects of azithromycin on QT interval prolongation are indeed there to see.

Whether it’s an isolated heart protocol or a telemetry investigation, there are numerous reports from preclinical studies showing that the azithromycin prolongs QT interval under certain conditions. Additional investigations confirm the clinical database—the compound is thankfully associated with very little proarrhythmic activity.

Filed under: Drug Safety Services, Langendorff Heart, Telemetry | No Comments

FDA Rejects Xarelto for Second Time in Less Than a Year

Posted by CorDynamics on March 05th, 2013

FDA Denies Xarelto for Expanded Indications for Acute Coronary Syndromes

The FDA rejected Xarelto (rivaroxaban) for a second time in less than a year as a drug therapy for patients with acute coronary syndromes.

Timeline of Concern

May 2012: By a narrow margin, an FDA Cardiovascular and Renal Drugs Advisory Panel recommended against expanding the marketing indications to prescribe Xarelto as an acute coronary syndrome therapy.

June 2012: The FDA confirmed panel opinion and denied expanding  Xarelto as an acute coronary syndrome therapy, citing concern over incomplete data.

  • The gaps occurred after nearly 1,300 patients dropped out of 15,000+-subject final-phase study and withdrew consent for access to their health information. There were also notable concerns about bleeding risks – in the absence of antidote – for rivaroxaban.

March 2013: FDA rejects Xarelto bid sending a second “complete response letter” which infers even more data is again requested.

Fast Facts
• Xarelto (rivaroxaban) is a factor Xa inhibitor—a blood thinner. The drug is already approved for stroke in patients with nonvalvular atrial fibrillation. It’s also indicated for those undergoing joint replacement surgery to prevent deep vein thrombosis.
• Acute coronary syndrome (ACS) is a catch-all phrase referring to conditions involving coronary artery obstruction.
• The studies under review evaluated the safety and efficacy of rivaroxaban in more than 19,000 ACS patients in addition to aspirin with or without thienopyridine therapy.
• If the panel had advised approval it would have meant an endorsement of treating ACS patients with combination therapy (aspirin, thienopyridine and rivaroxaban).

What Does This Mean for Drug Developers?
The earlier potential cardiovascular questions can be answered the better.

Investing in thorough safety and efficacy studies from preclinical all the way through the clinical phases of drug development is key.

Filed under: Atrial Fibrillation, Drug Safety Services, Preclinical Consulting Services | No Comments

Spotlight: FDA Approves Orphan Drug for Rare Cholesterol Disease

Posted by CorDynamics on January 14th, 2013

When the FDA gave the green light to an orphan drug with approval of Juxtapid (lomitapide) it marked a 16-year high of drug approvals by the US Agency in 2012.

Thirty-nine new chemical entities were approved last year, with many of them being therapies for rare diseases. This underscores our industry’s increased focus on specialized, niche products.

FDA Orphan Drugs Rare Diseases Cholesterol

The drug meets the previously unmet needs of patients, usually children. with homozygous familial hypercholesterolemia (HoFH) who are unable to remove LDL cholesterol—often known as the “bad” cholesterol—from the blood.

Lomitapide works as an anti-cholesterol agent by inhibiting the microsomal triglyceride transfer protein. This moiety is necessary for assembly of very low density lipoprotein (VLDL) in the liver. VLDL is converted in the blood stream to LDL. Patients with HoFH are at severe risk for atherosclerosis (hardening of the arteries), which causes heart attacks, strokes and other serious vascular conditions usually before the onset of puberty.

HoFH occurs at a rate of approximately 1:1,000,000 in the general population.

Points to Consider

  • The efficacy of Juxtapid increases in conjunction with diet changes and other cholesterol lowering treatments.
  • The FDA is requiring three post-marketing studies, including a long-term registry of HoFH patients taking Juxtapid to determine the long-term safety.
  • Due to lingering questions on the safety of Juxtapid, the FDA insisted a ‘black-warning’ be added to the drug’s labeling.
Filed under: Drug Safety Services, Heart Failure | No Comments

Zofran, The FDA and Return of Cardiovascular Culprit: QT Interval Prolongation

Posted by Michael Gralinski, Chief Executive Officer at CorDynamics on December 05th, 2012

I’m often asked: Why should our project team expend finite resources on cardiovascular safety studies for an oncology therapy or GI compound?

Today’s FDA removal of the highest dose form of Zofran (ondansetron) from the market is a prime example.

Cardiovascular Safety Studies Find QT Interval Prolongation

Case Study

The gastrointestinal drug ondansetron is a 5-HT3 (serotonin type 3) receptor antagonist indicated for use in the prevention of chemotherapy-induced nausea and vomiting and post-operative nausea and vomiting.

This is an interesting scenario since ondansetron is often used as adjuvant therapy. For example, an oncology patient has nausea and vomiting induced by chemotherapy treatment. Their physician prescribes ondansetron to mitigate these severe GI side effects.  On top of all these issues, one certainly wishes to avoid prolongation of the QT interval. Thus, Drug 1 (cancer treatment) leads to Drug 2 (treatment for the side effects of Drug 1), which is what causes cardiac effects.

Preclinical QT Interval Prologation with Ondansetron

The literature demonstrates that preclinical models are predictive for the electrocardiographic effects of ondansetron. The FDA stated today that the 32 mg, single IV dose should be avoided due to the risk of QT interval prolongation, which can lead to Torsades de Pointes, an abnormal, potentially fatal heart rhythm. Learn more about QT Interval prolongation. 

Our team has published and worked extensively with preclinical models designed to detect the propensity for QT interval prolongation early in the discovery, preclinical and phase I stages. View data.

Serotonin is involved in many areas of human physiology. Drugs that alter the pharmacology of serotonin must be interrogated for cardiovascular effect regardless of the target for therapy.

Filed under: Drug Safety Services, Electrophysiology, Hemodynamics, Langendorff Heart, Telemetry | No Comments

Who Regulates Drug Safety and Drug Development Better—the FDA or the EMA?

Posted by Michael Gralinski, Chief Executive Officer at CorDynamics on September 26th, 2012

The answer: It depends on who you ask.

The FDA versus the EMA (European Medicines Agency) is a continual debate. Different analysts have different opinions that seemingly change weekly.


What is true, is that both the FDA and the EMA have:

• the tough job of regulating drug development to ensure the approval safe and effective therapies.
• their own set of policies, procedures and guidelines.
• their own governing bodies, growing bureaucracies and shrinking budgets.
• vigilantly regulated drug safety with a keen eye on cardiovascular safety.

Yet with all this in common, why do the FDA and EMA sometimes come to different conclusions?

Many say it’s because the healthcare environments are different between the US and Europe, as well as their vastly different legal systems.

Case Study #1: FDA Says Ok, EMA Says No Way
The weight loss drug, Qysmia, earned FDA approval in July. BUT, Qysmia’s sponsor expects the EMA to recommend against approval based on numerous concerns, including the effects of one of the drug’s two main ingredients, phentermine, and the link to possible heart valve damage.

Case Study #2: EMA Says Yes, FDA Says Not Yet
An advisory panel recently recommended approval of the new anti-clotting drug Eliquis. BUT, the FDA rejected the drug for the second time this past June, citing the need for more information.

What to do?
Outsource to contract research organizations experienced with the ins and outs of both agencies and their specific guidelines—especially when it comes to cardiovascular issues.

I know the FDA. Fortunately, my colleague, Dr. Franz Hock, knows the EMA. While neither of us is so bold as to claim the ability to predict FDA and EMA decisions, we do typically know what cardiovascular questions they will ask and what information they will need to make their decisions. Once you know that, finding the answers gets a bit easier.

Filed under: Drug Safety Services, Preclinical Consulting Services | No Comments