Redefining Clinical Trials - Cancer

Redefining Clinical Trials for Cancer Treatment

A decade ago it took tens of millions of pounds and many years to sequence the compete genome of one individual. Now it takes a few hundred pounds and a couple of days to decode the entire DNA of a cancer cell. The rapid pace of change in DNA sequencing is leading to a transformation in the diagnosis and treatment of cancer. Scientists predict that  in the coming decade every cancer patient will receive a genetic profile of their disease.

An era of personalised medicine where patients receive tailor-made treatments based on their DNA rather than their just their symptoms could end the one-drug-treats-all approach to cancer treatment, which has failed many patients in the past.

The revolution will also mean that the classic method of testing new drugs and treatments based on large-scale clinical trials with thousands of patients will be replaced by a more targeted approach focussed on a smaller number of individuals with known genetic profiles.

Rapid DNA sequencing will usher in a new era of discovery where cancer drugs will be tailor-made for those patients based on the type of DNA mutations carried within their tumours.

“In part it might signal a significant shift in the way medicine is performed for cancer in the 21st Century,” said Professor Alan Ashworth chief executive of the Institute of Cancer Research in London which has just opened a new tumour profiling unit to rapidly sequence the DNA of cancer samples.

Professor Ashworth sais that, “None of this is science fiction. It’s happening in a number of places around the world but we feel it will be absolutely routine within the next five to ten years for every cancer patient,”. It could mean that drugs designed for one type of cancer will be used in the treatment of a quite different cancer as scientists uncover common biochemical pathways that link one disease to another.

Also, It opens up the possibility of using drugs in a context in which they were not originally developed and It could also change the whole approach to drug development and clinical trials.

Instead of having to rely on large “phase-3” trials involving several thousand patients followed for many years to determine small, statistically significant improvements, doctors could go straight to a new therapy based on their discretion, knowing that a drug can target a particular DNA abnormality.

In the past, drugs have been developed with large, phase-3 clinical trials involving thousands of patients and working out what is best for the average patient. But the recent trend is that to look at what is best for the individual patient (in specific). However, It may be that in certain rare cancer types, a drug might be considered effective, even though there may well never be clinical trial evidence to prove it,”.

Classical Clinical Trials

Classical clinical trials have essentially failed certain types of cancer patients, such people with tumours of the pancreas and lung, where the improvements in treatment have been minimal. Similarly, some existing cancer therapies are known to be ineffective in a large number of patients who routinely receive the treatments – but DNA profiling could help to end this harmful waste. In chemotherapy for women with breast cancer, for instance, only about one in ten receives any benefit from the treatment. So that means we are massively over-treating the population – nine out of ten receive essentially no benefit. Now the design of clinical trials must based on to deliver the drugs for success rather than failure and also to work them effectively on more patients for a longer time.

Drug resistance is one of the biggest problems to emerge from the use of new drugs targeted at certain DNA profiles. Resistance is a Darwinian process – cancer cells continue to mutate and those that are resistant survive the therapy and quickly spread around the body.

The biggest obstacle to personalised medicine is really resistance, and understanding what causes resistance. But this is not black magic it is something that can be defined, quantified and understood, and then exploited.

Some people have taken this as a sign that personalised medicine isn’t working but the answer to that is that it’s still early days. These drugs have just been developed, we’re working out how to use them and we’re starting to understand what the resistance mechanisms are. It’s going to be much more complicated than giving a single drug and getting a cure.

Personalized medicine could actually save the NHS money in the long term if it prevents patients from developing metastatic cancers that have spread from the original site of the tumour.

It costs about £100,000 to treat a woman with metastatic breast cancer. We can do DNA profiles for a few hundred pounds. The clinical management costs will far outweigh the diagnostic costs.

I think with early-stage disease, we will be curing more people. With advanced disease, we are talking about keeping people alive, and more importantly well, for longer.

Reference:

http://www.independent.co.uk/news/science/forensic-cancer-treatment-personalised-drugs-therapy-becoming-a-reality-with-hopes-for-improvement-in-survival-rates-8470563.html

Comparative Effectiveness - Clinical Perspective

Robert Temple, M.D., Deputy Center Director for Clinical Science provides his perspectives about how comparative effectiveness (i.e., comparing two drugs on various aspects) and their approach is not always effective.

Comparative effectiveness is on everybody's mind, and that makes sense. After knowing that a drug works, usually the most important questions physicians, and patients have are:  how well does this drug work compared to the alternatives that I could use; is it better, worse, or the same.  

So the desire to have comparative data, broadly referred to as comparative effectiveness research, is not surprising. The main difficulty with doing comparative studies is that the effects of most drugs, while valuable, are not very large, so that even showing a difference between the drug and no treatment (a placebo treatment) is not easy. Showing a difference between two effective drugs, a difference much smaller than the difference between a drug and no treatment, is very challenging and will usually need a very large study. Comparative data do exist that show advantages for some members of a class over others, but they are not common.

Comparative effectiveness studies that were successful

Within a class of drugs like antidepressants or antipsychotics, there are relatively few cases where we have been able to say that one drug is better than another; however, there are a few.

The antipsychotic drug clozapine, is generally thought to be more effective than other drugs in its class, however, it has a toxicity that no other members of the class have. Clozapine causes a marked decrease in the number of certain white blood cells. But it was shown to work in people who did not respond to other drugs.  This showing was critical to its approval.

Some drugs that inhibit platelets in patients with coronary artery disease have been studied in trials that compared the new drugs with an older drug. In some cases, the newer drugs had better effects, reducing the rate of heart attacks, though sometimes causing more bleeding. It is fairly common for a new cancer drug to be more effective than an older therapy.

There is a popular class of anti-hypertensive drugs called angiotensin receptor blockers. With considerable effort, and quite large studies, two companies have shown that their drug had a larger effect on blood pressure than other members of the class.

Individualized response studies

There is some hope that instead of doing large, randomized trials to show differences, between treatments, observational studies, i.e., epidemiologic data, can be used to do this. There is considerable disagreement on whether this is possible. My belief is that any differences between effective drugs are likely to be very small and can be credibly detected only in randomized trials. Whether pooling the results of multiple controlled trials (meta-analyses) will work is an area for discussion, but to do this you need many trials with the same comparison, a rare occurrence.

A kind of study that I think has a lot of potential is one that is almost never done: take people who have not responded to one drug, and then randomize them back to the drug that didn't work and to another drug. This is particularly interesting when the two drugs are in the same pharmacologic class.

There is a widespread relief that people respond different to similar drugs. Ask most physicians and they will tell you that there are individualized responses to treatments; some people do better on one drug than another very similar drug  and you don't always know the reason. They would expect that to be the case for pain medication (e.g., NSAIDS) or anti-depressants. If it is really true that people who don't respond to one member of a drug class actually respond to another member of the class, we can design the perfect study to test this.

For example, you could take people who don't respond to a migraine drug and randomize them back to a new migraine drug, the old migraine drug the one they didn’t respond to, and a placebo. If it's true that there are individual differences that are important, then the new drug ought to be able to show its advantage over the drug that didn’t work.

I am aware of only a few studies that have ever tried to do this:

• Clozapine, as I noted, is marketed because it was shown to work in people who had failed standard anti-psychotic therapy.
• Years ago, CDER was very worried about the first angiotensin-converting-enzyme inhibitor, captopril, because it caused agranulocytosis at high doses. FDA would probably not have approved it except that there was a trial in people who had failed what was then considered the best available therapy, “triple therapy,” a combination of reserpine, hydralazine, and a diuretic. Patients who had failed to respond to this treatment or to randomized back to triple therapy or to captopril; captopril dramatically beat the triple therapy. Captopril was then approved for patients who had failed triple therapy.
• More recently, Merck did a study in which they took people who had failed on Celebrex, a non-steroidal anti-inflammatory drug, and randomized them to Celebrex and to Vioxx. The company hoped, and I’m sure expected, that the people who failed Celebrex would respond better to Vioxx. The study, however, showed that there was no difference at all between the two drugs. Based on that study, it remains to be seen whether there are individual differences in response to anti-inflammatory drugs.

The question of whether a person who doesn’t do well on one member of a drug class might respond better to a closely related drug or drug of a different class is obviously an interesting and very important one. It still surprises me that this kind of study is rarely done.

Evaluating side effects

A closely related area of interest is whether, if a drug causes a side effect another member of the drug class, or a drug of a different class can be substituted and not cause the side effect. Again, this is a type of study that is very rarely done. But it is an interesting and therapeutically important question.

It has been shown that anti-depressants cause poor sexual function in women -- a common and significant effect. But do all anti-depressants have this effect or have it to the same extent? In one study, people who had sexual dysfunction while taking an anti-depressant were randomized to the anti-depressant that caused that dysfunction and to bupropion; bupropion, a pharmacologically different drug, didn't cause the sexual dysfunction. While the result was not really a surprise, the fact that the study was actually done was unusual.  There would seem to be a great many opportunities for such studies.

I would like to see more of these relatively small, easily-designed studies. They are not hard to conduct and the data have in some cases proved important.

Reference:

http://www.fda.gov/Drugs/NewsEvents/ucm295040.htm

Ethical Riddles - HIV Research

Boghuma Kabisen Titanji is a medical doctor and her research into HIV drug resistant viruses seeks to better understand the mechanisms of drug resistance and to identify new ways of targeting resistant viruses.

During the course of her research, Titanji met a woman named Celine who forever changed the way she thinks about the people who sign informed consent agreements to be research subjects. Ever since, Titanji has been a vocal advocate for ethical medical research, calling for researchers to find less exploitative ways to study diseases in developing countries.

In one of her talks delivered at TED information sharing sessions, she is more concerned about the following key factors that needs to be given more importance while conducting studies especially in the Developing countries.

1. Informed consent - The information contained in IC's which are provided to trial participants needs to be available efficiently in linguistically and acceptable formats.  

2. Standard of care - Needs to be improved in case of developing countries. 

3. Ethical Review - Effective system needs to be incorporated and its quite important especially in case of developing countries.

4. Public Accountability

5. The research which the pharmaceutical companies and funding agencies perform should be made available/accessible to clinical trial participants for future medical support.

To listen to her talk, please click on the following link.

Ethical Riddles in HIV Research

Hepatitis C Drug treatment - Failure

Hepatitis C - Drug Treatment failure leads to death of a patient during Clinical Studies.

Hepatitis C is a viral disease that leads to swelling (inflammation) of the liver.

For more detailed information on the symptoms of the disease, symptoms and treatment, refer to the Pub Med Health

Information (Updates) Regarding failure in Clinical Studies can be found below.

Source: Nature.blogs.com

Bristol-Myers Squibb has halted development of a potential hepatitis C drug after nine participants in a clinical trial of the therapy were hospitalized and one died (see press release).

Hepatitis C (HCV) is a chronic viral infection transmitted via blood and, occasionally, other bodily fluids. In a large proportion of cases, patients develop chronic liver disease, which can remain symptomless for decades. Cirrhosis and cancer occur in a number of cases, leading to a 1–5% death rate. The US Centers for Disease Control estimates that approximately 3.2 million people in the United States are living with chronic HCV infection, making a new and improved HCV drug a potentially very profitable investment.

Bristol-Myers Squibb (BMS), based in New York, acquired the rights to the drug BMS-986094 (formerly known as INX-189) when it bought Inhibitex, based in Alpharetta, Georgia, for US$2.5 billion in January (see‘Pharma giants buy up hepatitis C hopefuls’). The drug works by inhibiting a polymerase enzyme called NS5B, which is essential for viral replication. It was being tested in a phase II clinical trial until 1 August, when BMS announced that they had voluntarily suspended the research (see press release). It has since been revealed that this was owing to suspected heart and kidney toxicity effects, although the company cautioned that a causal link between the drug and adverse effects has not been proven. Two trial participants remain in hospital (reported in the New York Times). Abandoning the drug amounts to writing off about $1.8 billion of what BMS paid for Inhibitex. After the news of the safety crisis broke, shares in BMS fell, reducing its market value by billions (see FierceBiotech).

This is a major blow for BMS, which had been hoping to capitalize on the multibillion-dollar market for a new HCV treatment. The company is just one of the competitors in a hot field that has seen some big acquisitions in recent years. In February, Gilead Sciences, based in Foster City, California, bought out Pharmasset, of Princeton, New Jersey, for $11 billion to take control of their hepatitis drug candidate (seeNature Biotechnology‘s news story — subscription required). In the same month, Enanta Pharmaceuticals, based in Watertown, Massachusetts, secured a hepatitis C drug-development deal with Novartis, based in Basel, Switzerland, with a $34-million up-front payment and another $440 million if the drug reaches required goals, plus a double-digit percentage of worldwide sales (see Xconomy). Roche, also based in Basel, bought Anadys Pharmaceuticals, based in San Diego, California, for $230 million in October 2011, after eyeing a hepatitis C drug in its pipeline (see Nature). These acquisitions had led to the share prices of other HCV drug developers to rise in anticipation of a buyout (see InvestorPlace).

For many years, the only available treatment for HCV was a combination of interferon-α and ribavirin. The interferon acted to boost the patient’s immune system, while ribavirin inhibited virus replication. A modified version of interferon-α, pegylated-interferon-α, which remains in patients’ bodies for longer, was introduced in 2001. But the treatment had severe side effects, including anaemia, severe depression and flu-like symptoms, and was not effective in all patients. Last year, two new drugs, boceprevir and telaprevir, were approved by the US Food and Drug Administration (FDA). Both of these drugs target HCV’s NS3-4A protease, which the virus needs to generate functional proteins. Both drugs, however, do have side effects. Because they are taken in combination with interferon-α and ribavirin to prevent the emergence of resistance, the side effects of the original treatment regimen are still a problem. Telaprevir was recently relabelled to take into account its potential for causing cardiac arrhythmias (FDA update) and boceprevir has been found to interact with HIV protease inhibitors, so co-administration is not recommended (FDA update).

Pharmaceutical companies are trying to find new drugs that are more effective and have fewer side effects. In addition to protease inhibitors, other potential drugs (including BMS-986094) act on the NS5B RNA polymerase enzyme, preventing amplification of viral RNA. Another class of drugs aim to stop viruses penetrating the host’s cells (see ‘New drug targets raise hopes for hepatitis C cure’).

Idenix Pharmaceuticals, based in Cambridge, Massachusetts, had a drug in trial that acted with a mechanism similar to that of BMS-986094. That trial has now been put on partial hold by the FDA as a result of the BMS trial failure (see press release). Shares in Idenix tumbled after the news was released (seeFierceBiotech and Business Week). There may still be hope for other NS5B inhibitors in the pipeline, as not all of them share the same mechanism of action as BMS-986094. Gilead has an NS5B inhibitor in phase III trials, and Vertex, also based in Cambridge, is working on a similar drug.

CORRECTION: An earlier version of this post incorrectly implied that Vertex and Gilead HCV drugs are being investigated by the FDA, when both companies have stated that they have not been contacted by the FDA (see Business Week).

Treatment for Tuberculosis

Combination Therapy for Multiple Tuberculosis (TB)

Pulmonary tuberculosis (TB) is a contagious bacterial infection that involves the lungs, but may spread to other organs.

TB is an infection caused by Mycobacterium tuberculosis and is one of the world’s deadliest diseases. It is spread from person to person through the air and usually affects the lungs, but it can also affect other parts of the body such as the brain and kidneys. According to the Centers for Disease Control and Prevention, nearly 9 million people around the world and 10,528 people in the United States became sick with TB in 2011.

Multi-drug resistant TB occurs when M. tuberculosis becomes resistant to isonazid and rifampin, two powerful drugs most commonly used to treat TB. Sirturo is the first drug approved to treat multi-drug resistant TB and should be used in combination with other drugs used to treat TB. Sirturo works by inhibiting an enzyme needed by M. tuberculosis to replicate and spread throughout the body.

“Multi-drug resistant tuberculosis poses a serious health threat throughout the world, and Sirturo provides much-needed treatment for patients who have don’t have other therapeutic options available,” said Edward Cox, M.D., M.P.H, director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research. “However, because the drug also carries some significant risks, doctors should make sure they use it appropriately and only in patients who don’t have other treatment options.”

Sirturo is being approved under the FDA’s accelerated approval program, which allows the agency to approve a drug to treat a serious disease based on clinical data showing that the drug has an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients. This program provides patients earlier access to promising new drugs while the company conducts additional studies to confirm the drug’s clinical benefit and safe use.

The FDA also granted Sirturo fast track designation, priority review and orphan-product designation. The drug demonstrated the potential to fill an unmet medical need, has the potential to provide safe and effective treatment where no satisfactory alternative therapy exists, and is intended to treat a rare disease, respectively.

Sirturo carries a Boxed Warning alerting patients and health care professionals that the drug can affect the heart’s electrical activity (QT prolongation), which could lead to an abnormal and potentially fatal heart rhythm. The Boxed Warning also notes deaths in patients treated with Sirturo. Nine patients who received Sirturo died compared with two patients who received placebo. Five of the deaths in the Sirturo group and all of the deaths in the placebo arm seemed to be related to tuberculosis, but no consistent reason for the deaths in the remaining Sirturo-treated patients could be identified.

Sirturo’s manufacturer, Janssen Therapeutics, will distribute the drug from a single source and will provide educational materials to help ensure the drug is used appropriately.

Sirturo’s safety and effectiveness were established in 440 patients in two Phase 2 clinical trials. Patients in the first trial were randomly assigned to be treated with Sirturo plus other drugs used to treat TB, or a placebo plus other drugs used to treat TB. All patients in the second trial, which is ongoing, received Sirturo plus other TB drugs. Both studies were designed to measure the length of time it took for a patient’s sputum to be free of M. tuberculosis (sputum culture conversion, or SCC).

Results from the first trial showed patients treated with Sirturo combination therapy achieved SCC in a median time of 83 days, compared with 125 days in patients treated with placebo combination therapy. Results from the second trial showed the median time to SCC was 57 days, supporting the efficacy findings of the first trial.

Common side effects identified in the clinical trials include nausea, joint pain, and headache

FDA provides a portal to India to ensure product safety on food and drug products



With offices in New Delhi and Mumbai staffed by technical experts and experienced investigators in food and medical products, FDA maintains close contact with India’s government, industries, trade associations, and scientific and academic communities. Consequently, India’s officials are better informed about FDA’s import requirements and the agency is able to share best practices involving the production of FDA-regulated products.

ICH-GCP in Drug Development Process

What is ICH-GCP guidelines in Clinical Trials / Research ?

The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe, Japan and the US to discuss scientific and technical aspects of drug registration. Since its inception in 1990, ICH has evolved, through its ICH Global Cooperation Group, to respond to the increasingly global face of drug development, so that the benefits of international harmonisation for better global health can be realised worldwide. ICH's mission is to achieve greater harmonisation to ensure that safe, effective, and high quality medicines are developed and registered in the most resource-efficient manner.

Bone Anchored Hearing Aid - Approved for Clinical Studies by FDA

Nytt implantat ersätter skadat mellanöra

Functionally deaf people can have normal hearing with a new implant that replaces the middle ear. The unique invention from Chalmers has been approved by the FDA for a clinical study. Last week was operated on the first patient.

The new instrument, which has been developed at Chalmers, the patient receives a barely six inches long implants implanted just behind the ear, directly against the skull. The technology utilizes the bone to conduct sound vibrations to the inner ear and called Bone Conduction Implant (BCI).

BCI implant will provide perfect hearing, even for those patients who are born without a middle, according to Bo Håkansson.

- The sound of your own voice you hear to 50 percent by using bone conduction, so you experience benlett sounds quite natural, says Professor Bo Håkansson at the Department of Signals and Systems, Chalmers.
He and his research team have developed a new, unique implant. Unlike the kind of benledningsapparat used today need a new hearing aid is not anchored to the skull with a titanium screw through the skin. The patient need not be afraid of losing the screw and avoid the risk of skin infections around the attachment.
The first operation on 5 December by Chief Mans Eeg-Olofsson, Sahlgrenska University Hospital, and went according to plan.
- When the implant was in place, we tested the function, and everything seems to work as intended so far. Now, the wound heal in four to six weeks before we can turn the hearing aid, says Måns Eeg-Olofsson, Medical Director of the project the past two years.
The technique is designed to handle mechanical damage to hearing, for individuals who have suffered from chronic ear infections, bone diseases or congenital malformations of the external ear, ear canal or middle ear. They often have great problems with hearing. For those rarely work regular hearing aids, which compensates for neurological problems in the inner ear. Bone-anchored devices can, however, provide a dramatic improvement.
Cochlea function may not be too bad to benledd hearing to work.
- Probably, the patient may have a reduction down to 30-40 dB even in the cochlea. How much reduction can be tolerated, we shall try to find out in the clinical study, says Bo Håkansson.

Making the quadratic internal speaker is small enough while effective has been the most difficult problem to solve.

If the technology works, the patients even more to win. According to previous tests volume gets around 5 decibels higher and treble quality better with BCI compared with previous bone anchored technique.
Within a month will premiere patient implant will be activated and adjusted according to the patient's hearing and wishes. Then follow the testing and inspections every three months until one year after surgery.
- Then we end with a new X-ray and new hearing tests. If all goes well, the operations of more patients place in parallel and relatively concentrated in the spring, says Måns Eeg-Olofsson.
The researchers expect to present the first clinical results in 2013. But when is benledningsimplantatet ready for the market?
- According to our plans, it can be done in only one or two years. To the new technology to reach widespread, massive investments already in the development stage, says Bo Håkansson.
Photo: Oscar Mattsson

Two parts - an external audio processor and an implant
The implant is barely six inches long. It is surgically placed just behind the ear, directly against the skull. The coil of the top end work inductively connected to the hearing aid external, visible component, an audio processor, the patient can easily attach or remove the head.
The external sound processor is held in the right place with the help of two magnets. Titanium screw through the skin (in other technology) is replaced by an inductive link that transmits ambient sounds through intact skin to a single receiver. The audio signal is passed down to a square speaker that is anchored in the bone near the ear canal. It produces sound vibrations that reach the cochlea sensory hair body through the skull.
Illustration: Emil Håkansson / Chalmers


Deaf people will have normal hearing and function with BCI
Hearing damage is the industrialized world's most common physical disabilities. If the problem is in the mechanism that will cause the sound to the inner ear - for example in the eardrum or middle ear bones - you can use the leg instead.Soon functionally deaf have normal hearing with the implant in the picture, called Bone Conduction Implant, BCI.
- The solution becomes very comfortable and aesthetically pleasing. Implant secure location inside the skull allows the patient does not need to think about being more careful than other people at eg water sports, explains Bo Håkansson, who leads the research project behind the invention.
Illustrati on Boid / Chalmers


Chalmers and Sahlgrenska in close cooperation since the 70's
in 1977 were provided three adult patients with titanium implants in the bone behind the ear at the ear clinic at Sahlgrenska hospital. This was the starting point for an intimate and long been a collaboration between Professor Bo Håkansson, ear physician and Associate Professor Anders Tjellström and Professor PI Branemark, known for his concepts of permanent anchoring of the implant in the bone, so called osseoimplantat.
The so-called Baha technology (Bone Anchored Hearing Aid) has gradually been refined since then and today helps more than 100 000 patients worldwide to hear better, and the more it becomes. Baha technology has never been spread so rapidly that today. The cross-disciplinary teamwork has survived intact for over 35 years.

More on BCI project
Besides Bo Håkansson and Måns Eeg-Olofsson involved the following persons in the project: Dr. Sabine Reinfeldt and doctoral Hamid Reza Taghavi and Karl-Johan Fredén Jansson from the research team at the Department of Signals and Systems, Chalmers University of Technology, and Professor Anders Tjellström and chief Joacim Stalfors, SU Sahlgrenska, and Professor Carina Johansson, dental department of the University of Gothenburg.
The research was funded by including Vinnova, the Swedish Research Council, National Association of Hearing, Regional Executive funding for R & D, Foundation Acta Oto-Laryngologica, Stingerfonden, Göteborg Medical Society and Kristina Stone's foundation.

Free Online GCP Training - Very informative


Dear Friends, Today I have shared the online learning system from AstraNova.

A Short Description about Astra Nova

Astra Nova Training is a UK-based training organization, which focuses on pharma and clinical research in-house training solutions through international network of training professionals. The primary goal is to ensure that companies and organizations worldwide have access to up-to-date and affordable pharmaceutical training in all of its aspects. 

Anti-diarrheal drug for HIV/AIDS patients

Fulyzaq is the second botanical drug approved by the agency

The U.S. Food and Drug Administration today approved Fulyzaq (crofelemer) to relieve symptoms of diarrhea in HIV/AIDS patients taking antiretroviral therapy, a combination of medicines used to treat HIV infection.

Diarrhea is experienced by many HIV/AIDS patients and is a common reason why patients discontinue or switch their antiretroviral therapies. Fulyzaq is intended to be used in HIV/AIDS patients whose diarrhea is not caused by an infection from a virus, bacteria, or parasite. Patients take Fulyzaq two times a day to manage watery diarrhea due to the secretion of electrolytes and water in the gastrointestinal tract.

Derived from the red sap of the Croton lechleri plant, Fulyzaq is the second botanical prescription drug approved by FDA. A botanical drug product is often a complex mixture derived from one or more plant materials with varying degrees of purification. In 2006, the FDA approved the first botanical prescription drug, Veregen (sinecatechins), a treatment for external genital and perianal warts.

“Currently, there are no FDA-approved therapies for HIV-associated diarrhea,” said Julie Beitz, M.D., director of the Office of Drug Evaluation III in FDA’s Center for Drug Evaluation and Research. “Fulyzaq may be helpful to HIV/AIDS patients with this troublesome condition.”

Just as for other types of drugs, the safety and efficacy of a botanical drug product are established through clinical trials. In addition, manufacturers of a botanical drug product must ensure rigorous control of raw materials, and good agricultural and collection practices, together with analytical testing of the complex mixture.

The safety and efficacy of Fulyzaq were established in a clinical trial of 374 HIV-positive patients on stable antiretroviral therapy with a history of diarrhea lasting one month or longer. The median number of daily watery bowel movements was 2.5 per day.  Patients who had diarrhea caused by an infection or a gastrointestinal disease were excluded from participating in the trials. Patients were randomly assigned to take Fulyzaq or a placebo twice daily.

The trial was designed to measure clinical response, defined as the number of patients who had two or fewer watery bowel movements weekly. Results showed that 17.6 percent of patients taking Fulyzaq experienced clinical response compared with 8 percent taking placebo. In some patients, a persistent anti-diarrheal effect was seen for 20 weeks.
Before treating patients with Fulyzaq, health care professionals should conduct proper testing to confirm the diarrhea is not caused by an infection or a gastrointestinal disease. Common side effects reported in patients taking Fulyzaq in the clinical trial were upper respiratory tract infection, bronchitis, cough, flatulence, and increased levels of the liver enzyme bilirubin.

Fulyzaq is distributed by Salix Pharmaceuticals, based in Raleigh, N.C. under license from Napo Pharmaceuticals, Inc. 

Veregen is marketed by Florham Park, N.J.-based PharmaDerm.

For more information:

• FDA Approved Drugs: Questions and Answers
• FDA: Drug Innovation
• FDA: HIV and AIDS Activities

FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

MBDD

Optimization through Model-based Drug Development Process

Here is a new creative model from Quintiles CRO for model based drug development process by the optimizing the biopharmaceutical development process to reduce the cost and time in order be able to release the drug into the market earlier.