January 31, 2014

FDA and Health Canada: Working Together for an Efficient Pathway for Drug Applications

Posted on January 31, 2014 by FDA Voice

By:  Robert Yetter, PhD

At FDA, we work closely with national regulatory agencies around the world on issues relating to the safety, efficacy and availability of medical products. An exciting example of such collaborative efforts is the Common Electronic Submissions Gateway (or CESG), an outcome of the US-Canada Regulatory Cooperation Council (RCC). Through a cooperative research and development agreement, FDA worked with our counterparts in Health Canada, to share technology that will make it more efficient for industry to submit applications to both the U.S. and Canada for the approval of pharmaceutical and biological products. A common infrastructure would enable industry to submit to both countries using the same electronic format for technical documents.

The RCC Initiative was announced in February 2011 by President Barack Obama and Prime Minister Stephen Harper. Its goals are to promote economic growth, job creation and benefits to consumers and businesses through increased regulatory transparency and coordination. The electronic submissions gateway is one such project designed to meet those goals.

So just what is this gateway? It’s an electronic “post office” that uses secure Internet connections to receive electronic versions of medical product applications and related documents from industry sponsors seeking regulatory approval. The technology was developed under contract, and implementation at FDA was led by the Center for Biologics Evaluation and Research.  FDA’s Electronic Submissions Gateway (ESG) has been in operation since 2006. It has now been modified to accommodate submissions from both Canada and the U.S. using the same interface and technology, and subsequently sending those submission transmissions to one or both regulatory authorities.

The collaboration on the Common Electronic Submissions Gateway has the potential to yield long-term positive outcomes for both FDA and Health Canada. The collaboration continues the work between the two regulatory partners to streamline both agencies’ submission requirements while maintaining consistency in regulatory requirements. It could also lead to cost reductions for regulated industry, which would not have to follow separate technical requirements for submission to the two countries.

We’re very proud of our work with Health Canada to make this technology accessible in a relatively short amount of time, going from concept to delivery in 26 months. This is yet another example of the steps FDA is taking as part of our Global Initiative, which envisions enhanced collaboration with our regulatory partners.

Robert Yetter, PhD, is the Associate Director for Review Management in FDA’s Center for Biologics Evaluation and Research


What is the purpose of liver function tests?

Provided by Nursing Times

Practice educator

31 January, 2014


Andrew Blann is a consultant at City Hospital, Birmingham, and senior lecturer in medicine, University of Birmingham.


Blann A (2014) Routine blood tests 2: what is the purpose of liver function tests? Nursing Times; 110: 6, 17-19.

The liver is the body’s largest single discrete organ. It has four major functions: metabolism and synthesis; excretion; storage; and the detoxification of potential poisons. These diverse functions mean that a single test does not give enough information to assess fully how the liver is functioning; at least five different liver function tests are required.

This article, part 2 in a four-part series, discusses the information on acute and chronic liver disease that these tests can provide, and how disease affects liver function.

  • This article has been double-blind peer reviewed
  • Figures and tables can be seen in the attached print-friendly PDF file of the complete article in the ‘Files’ section of this page


  1. The liver plays an important role in synthesis, excretion, storage and detoxification
  2. Its multiple metabolic and excretory functions mean disease of the liver can have serious consequences
  3. The most obvious indication of liver disease is jaundice, a sign of high levels of bilirubin
  4. Although the liver largely regenerates after damage, if damage is prolonged it loses its ability to do so
  5. There are few clinical situations where a diagnosis can be made based on a single blood test

The liver, the largest single discrete organ in the body, has four main functions and plays a major part in many metabolic and excretory processes. Due to its multiple functions, liver disease has numerous consequences, many of which can be detected and monitored with blood tests known as liver functions tests (LFTs).

Main functions of the liver


The liver produces and exports many proteins and lipids into the blood, so reduced levels of certain proteins (such as albumin and clotting proteins) may indicate damage to the liver. The liver also synthesises fatty acids, triacylglycerols and cholesterol, but the levels of these lipids are not regarded as markers of liver function.


When red blood cells die much is recycled, and what cannot be recycled is converted into bilirubin. Some bilirubin moves as bile into the gall bladder, while some immediately flows down the bile duct and through the duodenum, colouring the faeces brown.

The liver plays a significant role in removing excess nitrogen from the body through the production of urea.


Glucose is converted into the polysaccharide glycogen, which is stored in the liver. When there is too much glucose, it is converted into fat, which can be deposited in the liver and elsewhere. The liver also stores iron, vitamins, and copper.


In addition to synthesis and recycling, the liver has a role in detoxification. This includes metabolising plant, animal and fungal toxins (such as the fungal aflatoxin), as well as drugs and medication.

Liver disease

To carry out its diverse metabolic tasks, the liver uses several enzymes (Table 1). These help to link many of the liver’s functions to specific or non-specific tests; for many, the most obvious indication of liver disease is jaundice, a sign of high bilirubin levels.



Jaundice is a clear sign of liver disease, and is present when blood levels of bilirubin are so high (generally greater than 40mmol/L), that it enters the skin. This is most apparent in the sclera (white) of the eye. Jaundice is also called icterus and can develop in three ways: haemolytic, following red cell destruction; damage to liver cells; and failure to excrete bile, most likely due to obstruction.

At such high levels in the blood, this bilirubin finds its way to the kidney and into the urine, which becomes dark yellow and possibly orange/brown; this is an additional important clinical sign.


This common condition is caused by obstruction or stenosis of the bile duct by, for example, gallstones or a tumour. This prevents the liver and biliary system from excreting bile, leading to obstructive cholestasis.

Inflammatory cholestasis occurs when inflammation of the bile duct prevents bile from passing into the duodenum; the liver continues to generate bile, which fills the gall bladder leading to congestion. Once the gall bladder is full, bile cannot leave the liver and it passes into the blood causing jaundice. A further sign of cholestasis is a change in the colour of the faeces from brown to grey, a likely indication that bile is not entering the intestines.


If damaged, such as after a viral infection or exposure to a poison, the liver has a remarkable capacity to regenerate.

However, if the damage is prolonged, for example due to a chronic infection, the renewal processes may be unable to continue regenerating functioning liver cells, leading to fibrous tissues being deposited instead. Cirrhosis can be the end result of several lengthy pathological processes, including: autoimmune diseases; chronic hepatitis virus B infection; longstanding biliary obstruction; and alcohol misuse.

Eventually, the loss of functioning cells may lead to chronic liver failure, and possibly liver cancer.


Ascites is the excessive accumulation of plasma-like fluid in the peritoneal cavity. In up to 75% of patients, it is a consequence of advanced cirrhosis leading to portal hypertension. Other causes include heart failure, cancer and inflammation (Senousy and Draganov, 2009).


The primary malignancy of the liver is hepatocellular carcinoma (HCC). According to Cancer Research UK (2014), it makes up 1.3% of cancers, and well over 3,000 new cases arise each year.

HCC is also sometimes referred to as hepatoma, but technically this means a mass within the liver that may not necessarily be a malignancy.

The vast majority of liver cancer occurs in the liver cells (hepatocytes) themselves; cancer of the bile ducts - cholangiocarcinoma - is less common.

The main causes of liver cancer are chronic viral infection (hepatitis B and C) and long-term alcohol misuse. The key laboratory test for this type of cancer is alpha-fetoprotein (AFP); however, if the liver is the site of a secondary cancer (metastasis), AFP will be negative.

Fatty liver (steatosis)

Fat is effective for storing energy, and large deposits can be found in various parts of the body, such as around the heart and liver.

However, if fat intake is excessive, in certain rare metabolic conditions and if alcohol is misused, fat starts to be stored in the liver. In the absence of alcohol misuse, this leads to non-alcohol fatty liver disease, which in its mild form is described as steatosis.

The damage caused by lipid overloading leads to hepatocellular damage, inflammation and fibrosis, and the disease transforms to non-alcoholic steatohepatitis (NASH). This progresses to cirrhosis in about 5-8% of patients within five years, and may be complicated by hepatocellular carcinoma and liver failure (Adams and Angulo, 2006). NASH may be secondary to a number of conditions including diabetes, impaired fasting glycaemia, malnutrition, hypertension and obesity.

There are many other less common liver diseases, some of which are in Table 2.


Liver function tests

The interpretation of LFTs is complicated: there are few examples of clinical situations where a single blood test is sufficiently reliable to diagnose a precise disease, so practitioners need to gather as much information as possible before making a clinical judgement.

Aspartate aminotransferase (AST) and alanine aminotransferase (ALT)

Increased levels of these enzymes are traditionally seen as markers of damage to liver cells, which could have any one of several causes including infective agents, autoimmune disorders and toxins.

Infections with microbial pathogens all cause an increase in AST and/or ALT, although the latter is better for monitoring viral activity in chronic hepatitis B and C as it is released from damaged hepatocytes more easily.

AST and ALT are found in many non-liver cells, including skeletal and cardiac muscle, so raised levels following a heart attack do not necessarily imply liver disease. Similarly, raised AST is commonly found in haemolytic anaemia as this enzyme is present in red blood cells. Another blood test, lactate dehydrogenase (LDH), can be helpful in confirming the diagnosis of haemolytic anaemia.

Many drugs and toxins can also raise AST and/or ALT levels. These include alcohol, industrial solvents and cholesterol-lowering drugs of the statin class.


This has been described as the only true LFT, as clearing this potential toxin is a major liver function. Although the most common non-hepatic cause of raised bilirubin is excessive haemolysis, true liver disease, such as Wilson’s disease, may also cause red blood cell destruction and anaemia.

Bilirubin in neonates deserves special mention. The neonatal liver is under-developed and shortly after birth may not be mature enough to process its own bilirubin. This may lead to hyperbilirubinaemia and jaundice, which should normalise within 2-3 days after birth as the liver matures.

Alkaline phosphatase (ALP)

The most common cause of raised ALP is obstruction of the bile duct or its tributaries (cholestasis), commonly caused by gallstones. Primary biliary cirrhosis and pancreatic malignancy also cause an increase in ALP levels.

The major non-hepatic source of plasma ALP is bone, and raised levels are found in the absence of liver disease in patients with metabolic bone disease, such as Paget’s disease. Increased ALP may also be present in a primary or secondary bone cancer (typically metastases from prostate and breast cancer).

Gamma-glutamyl transpeptidase (gamma-GT)

There are numerous hepatic and non-hepatic causes of raised gamma-glutamyl transpeptidase (gamma-GT); it is often present in: cirrhosis or hepatitis; haemochromatosis; HCC; and secondary cancer.

Gamma-GT levels are also influenced by several commonly used drugs, such as phenytoin, barbiturates, carbamazepine and alcohol, which make this test less reliable.

Comparing the LFTs

In paracetamol poisoning, AST needs to be considered alongside bilirubin in assessing prognosis using serial results, perhaps over a period of a week.

If the AST and bilirubin fall in parallel, it suggests hepatic recovery and good prognosis. However, a falling AST with a rising bilirubin indicates critical loss of hepatocytes and a poor prognosis.

The ratio of the aminotransferases can be helpful. An AST:ALT ratio greater than 2:1 implies alcohol misuse because of the release of mitochondrial AST due to damage from alcohol metabolites.

A rise in AST may also be compared with rises in ALP; if AST is higher, this is suggestive of hepatitis. ALP and gamma‑GT often rise and fall together in many conditions, but ALP is the better marker of biliary and bone disease and GGT of alcoholic disease.

Table 3 gives a synopsis of the LFTs.


● This article was adapted from: Blann AD (2013) Routine Blood Tests Explained. Keswick: M&K Update.


Adams LA, Angulo P (2006) Treatment of non-alcoholic fatty liver disease. Postgraduate Medical Journal; 82, 315-322.

Cancer Research UK (2014) Twenty Most Common Cancers.

Senousy BE, Draganov PV (2009) Evaluation and management of patients with refractory ascites. World Journal of Gastroenterology; 15, 67-80.


Abbvie completes largest phase III program of an all-oral, interferon-free therapy for the treatment of hepatitis C genotype 1




Jan 31, 2014

NORTH CHICAGO, Ill., Jan. 31, 2014 /PRNewswire/ -- AbbVie (NYSE: ABBV) announced the completion of its phase III clinical program and released results of four additional studies designed to assess AbbVie's investigational all-oral, interferon-free therapy with and without ribavirin (RBV) in patients with chronic genotype 1 (GT1) hepatitis C virus (HCV) infection. These results described below confirm previously reported AbbVie data and further demonstrate high sustained virologic response rates 12 weeks post treatment (SVR12) and tolerability in these GT1 patients.

AbbVie Phase III Clinical Program Results



Treatment Regimen



(12 weeks)

GT1b treatment-experienced


AbbVie regimen + RBV (n=88)



AbbVie regimen only (n=91)




(12 weeks)

GT1b treatment-naive


AbbVie regimen + RBV (n=210)



AbbVie regimen only (n=209)




(12 weeks)

GT1a treatment-naive


AbbVie regimen + RBV (n=100)



AbbVie regimen only (n=205)




(12 & 24 weeks)

GT1 treatment-naive 
and treatment-experienced with 
compensated cirrhosis


AbbVie regimen + RBV, 12 weeks (n=208)



AbbVie regimen + RBV, 24 weeks (n=172)




(12 weeks)

GT1 treatment-naive


AbbVie regimen + RBV (n=473)




(12 weeks)

GT1 treatment-experienced


AbbVie regimen + RBV (n=297)



"The outcomes of AbbVie's comprehensive phase III studies in 2,300 patients across 25 countries demonstrate how our investigational regimen performs across a broad spectrum of genotype 1 patients, including those with compensated liver cirrhosis," said Scott Brun, M.D., vice president, pharmaceutical development, AbbVie. "The high rates of response and tolerability of our regimen, coupled with the low rates of discontinuation are promising."

The AbbVie investigational regimen consists of the fixed-dose combination of ABT-450/ritonavir (150/100mg) co-formulated with ABT-267 (25mg), dosed once daily, and ABT-333 (250mg) with or without ribavirin (weight-based), dosed twice daily. The combination of three different mechanisms of action interrupts the HCV replication process with the goal of optimizing SVR rates across different patient populations. In May of 2013, AbbVie's regimen with and without ribavirin for HCV GT1 was designated as a Breakthrough Therapy by the U.S. Food and Drug Administration (FDA). AbbVie is on track to begin major regulatory submissions early in the second quarter of 2014. AbbVie will disclose detailed study results at future scientific congresses and in publications.

About Study M13-389 (PEARL-II)
PEARL-II is a global, multi-center, randomized, open-label, controlled study to evaluate the efficacy and safety of 12 weeks of treatment with AbbVie's regimen with and without ribavirin in non-cirrhotic, GT1b HCV-infected, treatment-experienced adult patients.

The study population consisted of 179 GT1b treatment-experienced patients with no evidence of liver cirrhosis: 91 patients randomized to the regimen without ribavirin for 12 weeks, and 88 patients randomized to the regimen with ribavirin for 12 weeks. In the ribavirin-free arm, 100 percent (n=91/91) of patients achieved SVR12, while 97 percent (n=85/88) achieved SVR12 in the ribavirin-containing arm.

The most commonly reported adverse events were fatigue and headache. Discontinuations due to adverse events were reported in none of the patients in the ribavirin-free arm and two (2 percent) patients in the ribavirin-containing arm. There were no patients in either arm of the study that experienced virologic relapse or breakthrough.

About Study M13-961 (PEARL-III)
PEARL-III is a global, multi-center, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of 12 weeks of treatment with AbbVie's regimen with and without ribavirin in non-cirrhotic, GT1b HCV-infected, treatment-naive adult patients.

The study population consisted of 419 GT1b treatment-naive patients with no evidence of liver cirrhosis: 209 patients randomized to the regimen without ribavirin for 12 weeks, and 210 patients randomized to the regimen with ribavirin for 12 weeks. Following 12 weeks of treatment, 99 percent receiving the regimen without ribavirin (n=207/209) and 99 percent receiving the regimen with ribavirin (n=209/210) achieved SVR12.

The most commonly reported adverse events were headache and fatigue. No patient discontinued study drug due to adverse events. Virologic relapse or breakthrough was noted in none of the patients receiving the regimen without ribavirin and 0.5 percent of patients receiving the regimen with ribavirin.

About Study M14-002 (PEARL-IV)
PEARL-IV is a global, multi-center, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of 12 weeks of treatment with AbbVie's regimen with and without ribavirin in non-cirrhotic, GT1a HCV-infected, treatment-naive adult patients.

The study population consisted of 305 GT1a treatment-naive patients with no evidence of liver cirrhosis: 205 patients randomized to the regimen without ribavirin for 12 weeks, and 100 patients randomized to the regimen with ribavirin for 12 weeks. Following 12 weeks of treatment, 90 percent of patients receiving the regimen without ribavirin (n=185/205) and 97 percent receiving the regimen with ribavirin (n=97/100) achieved SVR12.

The most commonly reported adverse events were fatigue, headache and nausea. Discontinuations due to adverse events were reported in two (1 percent) patients receiving the regimen without ribavirin and no patients in the ribavirin-containing arm. Virologic relapse or breakthrough was noted in 8 percent of patients receiving the regimen without ribavirin and 2 percent of patients receiving the regimen with ribavirin.

About Study M13-099 (TURQUOISE-II)
TURQUOISE-II is the first phase III study completed exclusively in GT1 cirrhotic patients investigating an all-oral, interferon-free regimen. It is a global, multi-center, randomized, open-label study evaluating the efficacy and safety of 12 or 24 weeks of treatment with AbbVie's regimen with ribavirin in cirrhotic, GT1a and GT1b HCV-infected, treatment-naive and treatment-experienced adult patients.

The study population consisted of 380 GT1a and GT1b, treatment-naive and treatment-experienced patients with compensated cirrhosis: 208 patients randomized to the regimen with ribavirin for 12 weeks, and 172 patients randomized to the regimen with ribavirin for 24 weeks. Following 12 weeks of treatment, 92 percent of patients (n=191/208) achieved SVR12. Following 24 weeks of treatment, 96 percent of patients (n=165/172) achieved SVR12.

The most commonly reported adverse events were fatigue, headache and nausea. Discontinuations due to adverse events were reported in four (2 percent) patients receiving the regimen with ribavirin for 12 weeks and four (2 percent) patients in the 24-week arm. Virologic relapse or breakthrough was noted in 6 percent of patients in the 12-week arm and 2 percent in the 24-week arm.

Additional information about AbbVie's phase III studies can be found on www.clinicaltrials.gov.

Globally, approximately 160 million people are chronically infected with hepatitis C[1]. AbbVie's multinational HCV program is the largest all-oral, interferon-free clinical program in GT1 patients being conducted to date[2]. GT1 (with subtypes 1a and 1b) is the most prevalent genotype worldwide.

AbbVie's HCV Development Program
The AbbVie HCV clinical development program is intended to advance scientific knowledge and clinical care by investigating an interferon-free, all-oral regimen with and without ribavirin with the goal of producing high SVR rates in as many patients as possible, including those that typically do not respond well to treatment, such as previous non-responders to interferon-based therapy or patients with advanced liver fibrosis or cirrhosis.

ABT-450 was discovered during the ongoing collaboration between AbbVie and Enanta Pharmaceuticals (NASDAQ: ENTA) for HCV protease inhibitors and regimens that include protease inhibitors. ABT-450 is being developed by AbbVie for use in combination with AbbVie's other investigational medicines for the treatment of HCV.

Safety Information for Ribavirin and Ritonavir
Ribavirin and ritonavir are not approved for the investigational use discussed above, and no conclusions can or should be drawn regarding the safety or efficacy of these products for this use.

There are special safety considerations when prescribing these drugs in approved populations.

Ritonavir must not be used with certain medications due to significant drug-drug interactions and in patients with known hypersensitivity to ritonavir or any of its excipients.

Ribavirin monotherapy is not effective for the treatment of chronic hepatitis C virus and must not be used alone for this use. Ribavirin causes significant teratogenic effects and must not be used in women who are pregnant or breast-feeding and in men whose female partners are pregnant. Ribavirin must not be used in patients with a history of severe pre-existing cardiac disease, severe hepatic dysfunction or decompensated cirrhosis of the liver, autoimmune hepatitis, hemoglobinopathies, or in combination with peginterferon alfa-2a in HIV/HCV co-infected patients with cirrhosis and Child-Pugh score ≥ 6.

See approved product labels for more information.

About AbbVie
AbbVie is a global, research-based biopharmaceutical company formed in 2013 following separation from Abbott Laboratories. The company's mission is to use its expertise, dedicated people and unique approach to innovation to develop and market advanced therapies that address some of the world's most complex and serious diseases. AbbVie employs approximately 25,000 people worldwide and markets medicines in more than 170 countries. For further information on the company and its people, portfolio and commitments, please visit www.abbvie.com. Follow @abbvie on Twitter or view careers on our Facebook or LinkedIn page.

Forward-Looking Statements
Some statements in this news release may be forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995. The words "believe," "expect," "anticipate," "project" and similar expressions, among others, generally identify forward-looking statements. AbbVie cautions that these forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those indicated in the forward-looking statements. Such risks and uncertainties include, but are not limited to, challenges to intellectual property, competition from other products, difficulties inherent in the research and development process, adverse litigation or government action, and changes to laws and regulations applicable to our industry.

Additional information about the economic, competitive, governmental, technological and other factors that may affect AbbVie's operations is set forth in Item 1A, "Risk Factors," in AbbVie's 2012 Annual Report on Form 10-K/A, which has been filed with the Securities and Exchange Commission.

AbbVie undertakes no obligation to release publicly any revisions to forward-looking statements as a result of subsequent events or developments, except as required by law.

[1] Lavanchy D. Evolving epidemiology of hepatitis C virus. Clin Microbiol Infect. 2011; 17(2):107-15.  
[2] Comparison based on review of data from www.clinicaltrials.gov for phase 3a programs of Gilead, BMS and BI as of November 15, 2013.


For further information: Media: Elizabeth Hoff, +1 (847) 935-4236, elizabeth.hoff@abbvie.com , or Javier Boix, +1 (847) 937-6113, javier.boix@abbvie.com, Investor Relations: Elizabeth Shea, +1 (847) 935-2211, elizabeth.shea@abbvie.com