May 22, 2013

FDA Rethinking Personalized Drug Trials

By David Pittman, Washington Correspondent, MedPage Today

Published: May 22, 2013

WASHINGTON -- The FDA will need to "turn the clinical trial paradigm on its head" in order to allow more specifically targeted, personalized drug therapies to get on the market faster, a top agency official said Tuesday.

"We are going to have to change the way drugs are developed. Period," said Janet Woodcock, MD, head of the FDA's Center for Drug Evaluation and Research.

Answering every question needed from regulators about targeted therapies -- such as who should receive the drug, at what dose, and with what expected side effects -- won't be possible in a traditional clinical trial, she explained at a luncheon hosted by the Personalized Medicine Coalition, a group of insurers, drugmakers and patient communities here whose goal is to "promote the understanding and adoption of personalized medicine concepts, services and products to benefit patients and the health system," according to its website.

Instead of embarking on traditional clinical trials, drugmakers and clinical investigators need to work in different ways to select patients for what will inevitably be smaller trials, she said.

"Ever smaller subsets of patients are being identified, and we're really going to have to put our heads together and figure out how do you study these small subsets of diseases," Woodcock said in a 45-minute speech on the FDA's efforts to advance the field. "What types of trials and development programs do you do? And when does a subset get so small that you're not going to be able to do a randomized trial?"

Advances in genomics has allowed drugmakers to develop not just a new breast cancer treatment, for example, but one that targets a specific genotype of that cancer like HER2, as was done with trastuzumab (Herceptin).

Anywhere from an eighth to half of companies' drug pipelines are targeted therapies, Woodcock said. About a third of new entities approved by the FDA last year had some type of genotyped biomarker in its marketing application.

Developments in cancer drugs, infectious diseases, and genetic disorders have led the way on such personalized therapies.

But in order to develop trials to test these drugs, the FDA and drug developers need a "new definition of clinical trials" that recognizes therapies will be targeted at subsets of conventionally defined diseases, Woodcock said.

Rather than doing a single trial in all patients with a particular disease, developers need to stratify patients into needed subsets based on certain biomarkers, she continued. Only then will trials be able to test the safety and effectiveness of their drug candidates.

The way trials were developed in the past should not influence or govern the way things are done in the future, Woodcock said.

For decades, the agency has requested two randomized, controlled, non-inferiority trials. But those may not be possible with the small number of patients possible in trials.

In order to identify these subset of patients -- which may be very few in number -- drugmakers may have to work together or work with third parties like patient advocacy groups to identify them, the FDA drug center head said.

"We haven't seen a lot of this so far," Woodcock said. "We're hoping that independent groups set up these trial networks and standing trials, so that then companies are comfortable coming together through a third party to do development of their drugs."

The personalized cystic fibrosis drug ivacaftor (Kalydeco), which treats the disease arising from the G551D-CFTR mutation, was developed through such a patient group network, Woodcock said.

But there are other challenges the agency and developers must tackle too.

Such targeted therapies have had difficulty receiving insurance coverage, in part because of their price. Woodcock noted this trend has slowed development of diagnostics that accompany such products.

Therefore, targeted therapies need to slow or stop chronic diseases and not just show a positive short-term benefit to silence critics. "If we can cure Hepatitis C, there's not going to be a peep from anybody because the cost effectiveness of that will be absolutely clear," she said. "Same with cancer."

The FDA is also thinking about how to translate prescribing information to providers, who want simple, easy-to-understand instructions.

"They want directions. They don't want education. They don't want to be taught genetics," Woodcock said. "They want [to know] 'what do I do. please tell me.' "

Therefore, diagnostics that accompany drugs and information in labeling needs to be detailed and accurate but also easily understood.

That path ahead won't be easy and will require a grand change in the way clinical trials are thought about by drug regulators and developers. "We're going into uncharted waters here," Woodcock said. "I think it's going to be a big challenge for everyone."


Hepatitis C: A 21st Century Success Story (Op-Ed)


Credit: Dreamstime

Dr. David Bernstein, North Shore-LIJ Health System

Date: 22 May 2013 Time: 03:38 PM ET

Dr. David Bernstein is chief of the Division of Hepatology / Center for Liver Disease at the North Shore-LIJ Health System, and a professor of medicine at Hofstra North Shore-LIJ School of Medicine. He contributed this article to LiveScience's Expert Voices: Op-Ed & Insights.

Hepatitis C has been called a silent epidemic: As the most common blood-borne viral infection in the country, it affects more than 7 million Americans — yet, most don't know they have it. But the condition can lead to the development of cirrhosis and liver cancer, and is the leading indication for liver transplantation in the United States.

Baby boomers have the highest rate of hepatitis C infection, so the Centers for Disease Control and Prevention (CDC) recently recommended that all people born between 1945 and 1965 get tested at least once for it. People with other risk factors for hepatitis C (e.g., previous intravenous drug users, previous cocaine users, recipients of blood transfusions before 1992, and people with tattoos and body piercings in places other than the ears) should also get tested, regardless of age.

Once hepatitis C is diagnosed, it is curable, unlike other common blood-borne viruses , such as hepatitis B and HIV. Advances in hepatitis C therapies have been rapid. The first therapy for hepatitis C infection consisted of interferon injections alone, with a cure rate of less than 10 percent. In the mid-1990s, a pill called ribavirin was added to injectable interferon, and cure rates increased to about 40 percent. For more than 10 years, once-weekly injectable interferon plus oral ribavirin for a course of 24 to 48 weeks was the standard treatment method.

The high prevalence of hepatitis C has led to a considerable effort to improve cure rates with newer therapies. The first step was to understand the mechanism of hepatitis C viral replication. After researchers determined the disease's molecular structure, they identified the two main classes of enzymes involved in hepatitis C replication: protease and polymerase inhibitors. As a result of that research, direct-acting medications were manufactured to inhibit those enzymes — thus preventing replication and promoting higher cure rates.

In May 2011, the U.S. Food and Drug Administration approved the first new hepatitis C therapies in a decade. Two new oral agents — boceprevir and telaprevir, from the class of drugs called protease inhibitors — were approved for use in combination with pegylated interferon and ribavirin. These new, triple-therapy regimens have seen cure rates as high as 70 to 75 percent. Therapy lasts from 24 to 48 weeks. Boceprevir and telaprevir are both taken three times a day for a time period ranging from three months to 44 weeks, depending on clinical circumstance for each patient.

The new protease inhibitors increased efficacy — and side effects . Telaprevir is associated with a rash that generally appears in the first four to eight weeks of therapy, as well as anal pain that can manifest at any time during treatment. Most patients are easily treated with topical creams and antihistamine pills. Boceprevir is associated with a bad taste in the mouth in almost all patients — though this is more of an annoyance than a problem. Most patients barely notice it. Both telaprevir and boceprevir are associated with the development of significant anemia, which can limit their use. The anemia can lead to fatigue and may require the use of growth factors — compounds that affect cell growth, maturity and differentiation — to alleviate symptoms.

Since the approval of boceprevir and telaprevir, drug development has been progressing rapidly. Many studies are evaluating the use of second-generation protease inhibitors, polymerase inhibitors and NS5A inhibitors in various combinations to treat all different types of patients with hepatitis C. In addition to new agents, shorter durations of therapy (eight or 12 weeks) and interferon-free, all-oral regimens are in development.

It is highly probable that an all-oral regimen for the treatment of hepatitis C genotype 2 and 3 will become available late this year or in early 2014, with similar efficacy as that of interferon-based therapies, but with fewer side effects and a shorter course. It is also likely that a new, second-generation protease inhibitor — simeprevir — and a first-in-class oral nucleotide analogue polymerase inhibitor — sofosbuvir — will be approved in early 2014.

Both of those new agents are given once daily and will be approved for use in hepatitis C genotype 1 in combination with interferon and ribavirin. The treatment duration for the new simeprevir-containing regimen will likely be 24 to 48 weeks, while the regimen with sofosbuvir will likely last 12 weeks. Neither of those new agents have any significant side effects, and cure rates should be higher than currently approved triple therapies.

After simeprevir and sofosbuvir are approved, many even newer agents are likely to come to market. It seems clear that all-oral therapy for the treatment of genotype 1 should be available sometime in 2015 or 2016. Compared to current regimens, all of the newer therapies offer higher cure rates, shorter duration of therapy and fewer side effects. A lot of work is underway to determine the best possible therapy for specific groups of patients. For example, specific regimens will likely be developed for each genotype, for patients with cirrhosis, for patients with kidney disease and for those who have had a kidney transplant.

With any luck, in the next decade, medical science should be able to treat and cure more than 90 percent of hepatitis C patients. The greater challenge is identifying patients — because most remain undiagnosed — and educating medical providers about the new therapies. Hopefully, the CDC screening guidelines will help. In addition to their other advantages, the newer therapeutic regimens may prevent the development of cirrhosis, liver cancer and the need for liver transplantation. The treatment and cure of hepatitis C will be one of the 21st century's major medical success stories.

Bernstein's disclosures are as follows:

Clinical-trial sponsors: Abbott, BMS, Gilead, Janssen, Vertex, Merck, Genentech

Consultant/speaker bureau: Abbott, Gilead, Janssen, Vertex, Merck


Frederick A. Nunes, MD, on trial results for difficult-to-treat patients with HCV

Provided by Healio

May 22, 2013

ORLANDO, Fla. — Frederick A. Nunes, MD, associate professor of medicine, at Penn Health Systems, discusses his presentation, “Interferon‐free Regimens of ABT‐450/r, ABT‐267, ABT‐333, and Ribavirin Achieve High Sustained Virologic Response 4 Weeks Post‐Treatment (SVR4) Rates in Patients With Chronic HCV Genotype 1 Regardless of Race, Ethnicity, or Other Baseline Characteristics” during Digestive Disease Week 2013.

Among HCV patients who are difficult to treat, including African-Americans, those with high BMI and insulin resistance, achieved a very high sustained response using three direct-acting antivirals and ribavirin, Nunes says.


P. Patrick Basu, MD, comments on RESTRAINT C trial results

Provided by Healio

May 22, 2013

ORLANDO, Fla. — P. Patrick Basu, MD, assistant clinical professor of medicine at Columbia University College of Physicians and Surgeons; division chief, department of gastroenterology and GI endoscopy at North Shore University Hospital in Forest Hills, N.Y., discusses his presentation “Romiplostim’s Effect to Optimize SVR With Telaprevir, Ribavirin, and PEG Interferon-Alfa 2A in Thrombocytopenic Cirrhotics With Chronic Hepatitis C. A Placebo Controlled Prospective Clinical Trial: RESTRAINT C Trial.”


Mindie H. Nguyen, MD, comments on demographics among hepatitis C patients

Provided by Healio

Added 2013-05-21

Mindie H. Nguyen, MD, MAS, associate professor of medicine at Stanford University School of Medicine. Discussing her poster Sa1069: High Prevalence of Hepatitis C Virus Infection (HCV) in Asian Americans in a Community Primary Care Clinic, during DDW 2013 in Orlando, Fla.

Mindie Nguyen, MD, on HCV demographics


Eric J. Lawitz, MD, reviews COSMOS trial with HCV genotype 1 patients

Provided by Healio

May 22, 2013

ORLANDO, Fla. — Eric J. Lawitz, MD, of the Texas Liver Institute at the University of Texas, San Antonio, discusses his late-breaking poster “SVR Results of a Once Daily Regimen of Simeprevir (Tmc435) Plus Sofosbuvir (Gs-7977) With or Without Ribavirin (RBV) in HCV GT 1 Null Responders” at Digestive Disease Week 2013....

He reports encouraging results for SVR among patients who underwent a 12-week regimen of simeprevir and sofosbuvir and were previously null responders to peginterferon and ribavirin.


Andrew Muir, MD, analyzes recent hepatitis C clinical trial results

Provided by Healio

May 22, 2013

ORLANDO, Fla. — Andrew Muir, MD, clinical director, hepatology at Duke University Medical Center, offers an update on the most current hepatitis C research that was presented at Digestive Disease Week 2013.

With many new drugs coming forward, Muir said he provides his patients with time frames on the availability of these medications, including the much-anticipated interferon-free regimens. By understanding the regimens, a patient’s liver disease and what’s right for them, he says individualizing plans allows clinicians to better guide patients on timelines and expectations.


European Medicines Agency Validates Gilead’s Marketing Application for Sofosbuvir for the Treatment of Hepatitis C


-- Once-Daily Sofosbuvir will Receive an Accelerated Assessment by EMA;

Designation Granted to New Medicines of Major Public Health Interest --

FOSTER CITY, Calif.--(BUSINESS WIRE)--May. 21, 2013-- Gilead Sciences, Inc. (Nasdaq: GILD) today announced that the company’s Marketing Authorisation Application (MAA) for sofosbuvir, a once-daily oral nucleotide analogue inhibitor for the treatment of chronic hepatitis C virus (HCV) infection, which was submitted to the European Medicines Agency (EMA) on April 17, 2013, has been fully validated and is now under assessment. The data submitted in this MAA support the use of sofosbuvir and ribavirin (RBV) as an all-oral therapy for patients with genotype 2 and 3 HCV infection, and for sofosbuvir in combination with RBV and pegylated interferon (peg-IFN) for treatment-na├»ve patients with genotype 1, 4, 5 and 6 HCV infection.

Chronic HCV is a major cause of liver cancer and liver transplantation in Europe and around the world. The current standard of care for HCV involves 24-48 weeks of therapy with RBV and peg-IFN, which has to be injected and is associated with significant side effects.

“The clinical and economic burden of untreated HCV is substantial and growing rapidly. An estimated five million Europeans are living with hepatitis C, the majority of whom have not yet been diagnosed or are not in care. In addition, many are not suited to receive the current treatment regimens,” said John C. Martin, PhD, Chairman and Chief Executive Officer of Gilead Sciences. “If approved, sofosbuvir has the potential to improve cure rates, while reducing the duration of HCV therapy and reducing or eliminating the need for interferon injections.”

The MAA for sofosbuvir is supported primarily by data from four Phase 3 studies, NEUTRINO, FISSION, POSITRON and FUSION, in which 12 or 16 weeks of sofosbuvir-based therapy was found to be superior or non-inferior to currently available treatment options or historical controls, based on the proportion of patients who had a sustained virologic response (HCV undetectable) 12 weeks after completing therapy (SVR12).

Review of the MAA will be conducted under the centralized licensing procedure, which, when finalized, provides one marketing authorization in all 27 member states of the European Union (EU). EMA has accepted Gilead’s request for accelerated assessment for sofosbuvir, a designation that is granted to new medicines of major public health interest. Although accelerated assessment could shorten EMA’s review time of sofosbuvir by approximately two months, it does not guarantee a positive opinion from the EMA’s Committee for Medicinal Products for Human Use (CHMP) or final approval by the European Commission. If approved, sofosbuvir could be available for marketing in the EU in the first half of 2014. Gilead submitted a U.S. regulatory application for sofosbuvir in April 2013.

Sofosbuvir is an investigational product and its safety and efficacy have not yet been established.

About Gilead Sciences

Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company's mission is to advance the care of patients suffering from life-threatening diseases worldwide. Headquartered in Foster City, California, Gilead has operations in North America, Europe and Asia Pacific.

Forward-Looking Statement

This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including the risk that EMA, the U.S. Food and Drug Administration and other regulatory agencies may not approve sofosbuvir, and that any marketing approvals, if granted, may have significant limitations on its use. Further, additional studies of sofosbuvir, including in combination with other products, may produce unfavorable results. In addition, even if approved, Gilead may not be able to successfully commercialize sofosbuvir, and may make a strategic decision to discontinue its development if, for example, the market for the product fails to materialize as expected. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in Gilead's Quarterly Report on Form 10-Q for the quarter ended March 31, 2013, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.

For more information on Gilead Sciences, please visit the company's website at, follow Gilead on Twitter (@GileadSciences) or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.

Source: Gilead Sciences, Inc.

Gilead Sciences, Inc.
Patrick O’Brien, 650-522-1936 (Investors)
Cara Miller, 650-522-1616 (Media)


Integrating mental health care into HIV care

Public release date: 21-May-2013

Contact: Fiona Godwin
Public Library of Science

The integration of mental health interventions into HIV prevention and treatment platforms can reduce the opportunity costs of care and improve treatment outcomes, argues a new Policy Forum article published in this week's PLOS Medicine. Syvia Kaaya from the School of Medicine at the Muhimbili University of Health and Allied Sciences in Dar es Salaam, Tanzania and her international colleagues say that effective interventions exist for recognition and treatment of co-morbid mental disorders and can be implemented successfully by trained non- specialized providers in HIV care.

The authors say that interventions delivered by "task-sharing" would require "supportive supervision, monitoring, and feedback to inform quality improvement in comprehensive HIV/AIDS services providing mental health care" and that "multidisciplinary collaboration, coordination, and communication on common concerns are imperative for HIV services that integrate mental health care."

"Clinical depression, alcohol abuse, and HIV-associated neurocognitive disorders (HAND) are prevalent in people living with HIV and have negative consequences for HIV treatment outcomes," say the authors.

The five articles providing a global perspective on integrating mental health will be published weekly in PLOS Medicine beginning 30 April 2013.


Funding: LW's participation was supported in part by NIMH P20 MH086048. The sponsors had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing Interests: SM provides consultancy services at Mildmay Center (Uganda) for HIV care and for the Peter C Alderman Foundation (PCAF) for the care of Psycho-trauma victims. All other authors have declared that no competing interests exist.

Citation: Kaaya S, Eustache E, Lapidos-Salaiz I, Musisi S, Psaros C, et al. (2013) Grand Challenges: Improving HIV Treatment Outcomes by Integrating Interventions for Co-Morbid Mental Illness. PLoS Med 10(5): e1001447.doi:10.1371/journal.pmed.1001447



Sylvia Kaaya
Muhimbili University of Health and Allied Sciences,


No postings yet for HIV-positive Marines, sailors since policy change

By Matthew M. Burke

Stars and Stripes

Published: May 22, 2013

SASEBO NAVAL BASE, Japan — More than nine months have passed since the Navy decided to open up overseas and large-ship platform assignments to HIV-positive sailors and Marines, but not a single sailor has gotten such a posting.

The Navy’s Personnel Command is grappling with how to implement the instruction, which also covers blood-borne pathogens like hepatitis B and C.

Secretary of the Navy Ray Mabus handed down the policy in August 2012.

Personnel Command officials declined to comment on when the policy would actually take effect. Instructions can take time to implement, Personnel Command spokesman Lt. Cmdr. Rob Lyon told Stars and Stripes in an email.

“Navy Personnel Command recently completed a review of SECNAVINST 5300.30E, dealing with blood-borne pathogens, to ensure sailors affected will have the greatest opportunity to be successful, and any concerns by their receiving commands will be addressed,” Lyon said. “We will more than likely have more to discuss once the Milpersman article (implementation guidance) has been chopped by all parties.”

The policy effectively opened the assignments to HIV-positive sailors and Marines who are stable and have undetectable viral loads, which translates into minimal medical complications, Bureau of Medicine and Surgery spokeswoman Shoshona Pilip-Florea told Stars and Stripes in December.

The change was made possible because of medical advances that allow someone who contracts the Human Immunodeficiency Virus to live 20-30 years without adverse health effects with as little as one pill per day.

The implementation guidance gives medical personnel, detailers and receiving commanders a veto power for each request “based on the medical risks and needs of the Navy,” depending on whether the command in question could “support care,” Pilip-Florea said.Prospective recruits are still precluded from joining the services if they have the virus.

“The policy change better aligns the treatment of HIV with how other chronic illnesses are managed by Navy Medicine,” Pilip-Florea said. “In the case of HIV-positive servicemembers, these personnel and the services have put a lot of time and effort into their careers, and there is no medical reason for them not to be able to continue serving with pride.”

Pilip-Florea said the biggest change from the previous policy for HIV-positive sailors and Marines comes in added flexibility to case management. Those servicemembers would no longer be bound to stateside medical facilities and rules that dictated the frequency of clinical evaluations.

“The frequency of clinical evaluations for HIV-infected military personnel shall be determined by the member’s health status and by nationally accepted guidelines,” the instruction reads. “On a case-by-case basis, follow-up HIV evaluations may be performed at smaller naval medical treatment facilities with the results of those appointments being reported for tracking purposes.”

Pilip-Florea said Navy Medicine does not track cost data for specific conditions or long-term chronic illnesses so treatment costs — stateside versus overseas — are not known.

The Navy policy is unique, officials from the other service branches said.

The Army prohibits HIV-positive soldiers from being deployed or assigned overseas, according to Col. Andrew Wiesen, Western Region Medical Center’s chief of preventive medicine and the Army Surgeon General’s preventive medicine consultant. Any soldier found to be HIV positive while overseas will be reassigned stateside.

There are numerous reasons for the Army’s policy, including host-nation restrictions, the incompatibility of medical treatment and supply of medications with deployment, and protection of the blood supply, Wiesen said. Soldiers are often asked to donate blood in emergencies, and testing is not always reliable or complete in a deployed setting.

The Air Force also limits HIV-positive airmen to stateside assignments, according to spokeswoman Donna Tinsley. However, active-duty airmen can apply for a waiver if the receiving unit can provide the needed care.

“Essentially if the OCONUS (outside the continental United States) base is in need of the position and willing to take on the member and can provide adequate care, then it’s more likely to get accepted,” she said.

However, waivers are frowned upon, Air Force officials said. HIV-positive airmen are prohibited from donating blood.

“A major concern regarding deployment would be blood donation,” Air Force Capt. Candice Ismirle said. “Refusal to do so in cases of mass casualties, etc., will cause other members to question why and may make it difficult for the patient to keep their diagnosis confidential. Also, if there was pressure to donate blood and the patient did so, there could be HIV transmission in the deployed setting.”

Ismirle said all deploying airmen must be free of medical conditions that require special appliances, frequent treatment or follow-up by medical specialists or sub-specialists. The virus is disqualifying and requires a waiver to remain on flying status.

The Navy addressed the issue as HIV rates have risen steadily over much of the U.S. military in recent years. The Navy began testing for HIV antibodies in 1985.

The Navy found 128 HIV-positive sailors in 1992 and 315 in 2012, including 250 on active duty, Pilip-Florea said.

The Marine Corps had 90 HIV-positive Marines in 2012 — 71 on active duty — and the Air Force had 210 on active duty, officials said.

The Army could not provide up-to-date figures due to a transition between who keeps the figures, spokeswoman Margaret Tippy said. However, in 2008 there were more diagnoses than in any year since 1995, according to an Armed Forces Health Surveillance Center report from August.

Rates have remained high, the report said. In 2012, there were 333 active-duty HIV-positive soldiers.

OutServe, an association of active LGBT military personnel, declined to comment when reached by Stars and Stripes on Monday. The group applauded the effort when it was announced last year.

For more information, see the Secretary of the Navy instruction at