Hepatitis C Harm Reduction Project

Patient Assistance Programs for Hepatitis C Medications

I periodically get questions about financial assistance for hep C treatment from people who don't have health insurance.  Here's phone numbers and links to companies' patient assistance programs that provide free medications to people in this situation who meet their financial eligibility requirements:

Schering-Plough (PEG-Intron, Rebetron): Commitment to Care (website); phone: 1-800-521-7157

Roche (Pegasys, Copegus): Pegassist (website); phone: 1-877-734-2797

Valeant (Infergen): Infergen Aspire* (website); phone: 1-888-668-3393

Three Rivers (Ribasphere [generic ribavirin]): RibaCare (website); phone: 1-866-650-7422

* The Infergen Aspire website was down when I checked; Valeant recently acquired Infergen from InterMune, so there may be a few snags in the transition -- but my understanding is that Valeant intends to maintain a patient assistance program for Infergen.

Mounting Pressure on the FDA

The Food and Drugs Administration (FDA) announced on Friday that it will take five steps to review and improve its monitoring of drug safety (see New York Times story).  From the FDA's press release:

1. Sponsor an Institute of Medicine (IOM) Study of the Drug Safety System

An IOM committee, under an FDA contract, will study the effectiveness of the United States drug safety system with emphasis on the post-market phase, and assess what additional steps could be taken to learn more about the side effects of drugs as they are actually used. The committee will examine FDA's role within the health care delivery system and recommend measures to enhance the confidence of Americans in the safety and effectiveness of their drugs.

2. Implement a Program for Adjudicating Differences of Professional Opinion

CDER [the FDA's Center for Drug Evaluation and Research] will formalize a program to provide an improved process to ensure that the opinions of scientific reviewers are incorporated into its decision-making process. In most cases, free and open discussion of scientific issues among review teams, and with supervisors, managers and external advisors, leads to an agreed course of action. Sometimes, however, a consensus decision cannot be reached, and an employee may feel that his or her opinion was not adequately considered.

Such disagreements can have a potentially significant public health impact, so CDER's program provides for a review of the involved differing professional opinions by FDA and outside experts. An ad hoc panel, whose members were not directly involved in disputed decisions, will have 30 days to review all relevant materials and recommend to the Center Director an appropriate course of action.

3. Appoint Director, Office of Drug Safety

CDER will conduct a national search to fill the currently vacant position of Director of the Office of Drug Safety, which is responsible for overseeing the post-marketing safety program for all drugs. The Center is seeking a candidate who is a nationally recognized drug safety expert with knowledge of the basic science of drug development and surveillance, and has a strong commitment to the protection of public health.

4. Conduct Drug Safety/Risk Management Consultations

In the coming year, CDER will conduct workshops and Advisory Committee meetings to discuss complex drug safety and risk management issues. These may include emerging concerns for products that are investigational or already marketed. Examples of input that might be sought include whether a particular safety concern alters the risk to benefit balance of a drug; whether FDA should request a sponsor to conduct a particular type of study to further address an issue; what types of studies would best answer the question; whether a finding is unique to one product or seems to be a drug class effect; whether a labeling change is warranted and, if so, what type, and how to otherwise facilitate careful and informed use of a drug.

These consultations will include experts from FDA, other federal agencies, academia, the pharmaceutical industry and the healthcare community.

5. Publish Risk Management Guidances

By the end of this year, FDA intends to publish final versions of three guidances that have been developed by our agency to help pharmaceutical firms manage risks involving drugs and biological products. These documents are "Premarketing Guidance," covering risk assessment of pharmaceuticals prior to their marketing; "RiskMAP Guidance," which deals with the development and use of risk-minimization action plans; and "Pharmacovigilance Guidance," which discusses post-marketing risk assessment, good pharmacovigilance practices and pharmacoepidemiologic assessment.

These steps come late in a turbulent year for the FDA, which has increasingly struggled to respond to criticisms from the public, the media (including medical journals), Congress, and its own scientists on a range of issues:

Roche Gets Priority Review from FDA for Co-Infection

Roche announced today that the FDA had granted "a six-month Priority Review Status to the supplemental new biologics license application (sBLA) for Roche's combination therapy of Pegasys(R) (peginterferon alfa-2a) in combination with Copegus(R) (ribavirin, USP) for the treatment of chronic hepatitis C in patients co-infected with HIV. Roche submitted this file with the FDA in August 2004."

Roche's application is based on promising data from APRICOT, a study of almost 900 people co-infected with hepatitis C and HIV. Results from APRICOT were originally presented at an HIV conference in February, and published in the New England Journal of Medicine this summer (see abstract).

The results of APRICOT were striking:

Generic Biologics: The Biotech Empire Strikes Back

As I wrote yesterday, there’s every indication that generic biologics are coming – as far as Congress and the FDA are concerned, it’s just a question of how and when. But some leading biotech companies that market brand-name biologics see generic competition as a threat – and are using a number of strategies to derail them.

At the FDA meeting on scientific issues held earlier this month, Amgen called for a high standard in approving “follow-on” biologics:

Drugs produced by biotechnology "are unique products," Kenneth Seamon, Thousand Oaks-based Amgen's vice president for global regulatory affairs, told the FDA officers at the meeting in Gaithersburg, Md. "They must be held to the same high standards of safety, purity and potency as the innovator to insure patient safety."

Amgen urges caution in clearing biotech generics, Bloomberg News, 09/16/04

Amgen is the world’s largest biotech firm – according to Business Week, Amgen markets five drugs that each generate at least $1 billion in sales annually. Amgen’s blockbuster drugs include Aranesp (darbepoetin alfa), used to treat anemia – sometimes used during hepatitis C treatment to offset the side effects of ribavirin. Epogen and Procrit, other anemia drugs, are losing some of their patent protection this year, potentially clearing the way for generic versions. Amgen also markets Neupogen (figrastim), a drug sometimes used during hepatitis C treatment to offset certain side effects of interferon.

The Battle Over Generic Biologics

Teva’s entry into the hepatitis C market (see yesterday’s post) comes at a time of increased attention to the uncharted path to regulatory approval for generic versions of biologics – drugs made from living organisms (i.e., cells), such as interferon.

Biologics often require injection, and are typically several times more expensive than other types of drugs made solely from chemicals. Several biologics cost well over a thousand dollars a month for a course of treatment; at the high end, Imclone's Erbitux (used for colon cancer) can cost $20,000 a month. Biologics make up a rapidly growing proportion of drug costs, and have spurred debate among cancer doctors over whether the costs of these treatments exceeds the benefits to patients. While the expense of biologics in part reflects their higher manufacturing costs, the lack of competition ensures that companies can price their drugs as high as the market will bear. The call for generic biologics reflects these skyrocketing prices and pressures on insurers, government payers, and patients.

The FDA has claimed that it cannot approve any generic (or, to use their term, “follow-on”) biologic products until there’s more clarity on legal and scientific issues. The legal issues hinge on whether the FDA currently has regulatory authority to approve generic biologics under the 505(b)(2) provision of the Hatch-Waxman amendment to the Federal Food, Drug and Cosmetic Act. The 1984 legislation (formally known as the Drug Price Competition and Patent Term Restoration Act) established a new and simplified regulatory framework to guide the approval of generic versions of original (“brand-name” or “innovator”) drugs.

In short, generic versions no longer had to duplicate the results of clinical trials (studies that test a drug’s safety and efficacy in patients) that were conducted for the approval of the original drug. Generic companies simply had to demonstrate “bioequivalence” – that the generic drug behaved the same way in the body as the original drug. The theory was that the active chemical ingredient was identical, so safety and efficacy should be the same as long as the drugs were bioequivalent (for more background on Hatch-Waxman, and its effect on competition and pricing, see this 1998 report from the Congressional Budget Office [PDF version]).

However, this bioequivalence model has not been tested for biologics, where the same “active chemical” (which in this case could be a protein such as interferon or antibodies, or genetic material – e.g., RNA or DNA) could in theory behave differently in the body depending on how it’s manufactured.

Sandoz, the generics division of Novartis, recently forced the question by submitting Omnitrop, a generic version of human growth hormone (somatropin), for approval in Europe and the United States. Omnitrop would compete with brand-name versions of human growth hormone from Serono and Genentech.

Another Generic Ribavirin from Teva, but Where Are the Generic Interferons?

Reuters reports that the Food and Drugs Administration (FDA) has granted tentative approval to Teva Pharmaceutical's application to market generic ribavirin (see notice on FDA's website). Teva’s generic ribavirin will join three other generics already on the market, from Three Rivers Pharmaceuticals, Sandoz, and Warrick Pharmaceuticals (Schering-Plough’s generic subsidiary). Final approval will presumably come in October, upon the expiration of the 180-day marketing exclusivity period awarded by the FDA to Three Rivers and Sandoz (for background, see my earlier post, Generic Ribavirin Price Alert).

Teva’s tentative approval signals the potential for increased pricing competition for generic ribavirin. Back in April, prior to the introduction of generic ribavirin, the “branded” versions (Schering-Plough’s Rebetol and Roche’s Copegus) were significantly more expensive than today, based on prices from drugstore.com:

Notes on Hepatitis C treatment and research

A few links on current and future treatment:

1. Roche has filed an application to the Food and Drugs Administration to approve Pegasys (pegylated interferon) and Copegus (ribavirin) for treatment of hepatitis C in people co-infected with HIV (see press release). This filing is based on results of the APRICOT study (discussed here and here), which found that Pegasys/Copegus was more effective in co-infected people than Pegasys alone or standard interferon/ribavirin. The FDA has granted fast-track status to the application, with a decision expected in early 2005.

The value of this application is largely symbolic -- people co-infected with HIV can already take Pegasys and Copegus for hepatitis C treatment -- but may increase awareness of treatment options and efficacy in co-infected people and their health care providers. Roche has also requested FDA approval for the use of Pegasys in hepatitis B treatment (see press release). Roche's Pegasys currently has over 57% of the U.S. market for pegylated interferon, trailed by Schering-Plough's Peg-Intron (see Reuters article).

2. Vertex Pharmaceuticals announced the successful completion of the dosing phase of the first human study of VX-950, an investigational hepatitis C protease inhibitor (see press release). VX-950 was studied at a range of single doses in 'healthy volunteers' (people not infected with hepatitis C). Based on blood levels, the company believes the drug will achieve concentrations needed to suppress hepatitis C replication, and may be suitable for twice-daily dosing. Further studies in people with hepatitis C, given for up to 14 days, are expected to begin by the end of 2004.

Vertex recently met with a few community advocates and treatment writers to discuss their development plans for VX-950 and merimepodib, another drug being investigated for hepatitis C treatment in combination with pegylated interferon and ribavirin. I'll be writing in more detail about this meeting later. For more on hepatitis C protease inhibitors, see this article; for more on merimepodib, see here under 'IMPDH inhibitors'.

3. A new review published in the Journal of Hepatology suggests that amantadine may be useful as part of triple-combination therapy (with interferon and ribavirin) for people who do not respond to standard combination therapy (abstract here). Amantadine is an antiviral drug, like ribavirin, that has been researched extensively in hepatitis C treatment, with conflicting results. The authors of the review combined data from all available trials, finding that amantadine shows a marginal benefit in non-responders, but not in people who were treatment naive, or who initially responded to therapy but subsequently relapsed without achieving a sustained virologic response.

The authors conclude that these findings should be confirmed in new trials. For more on amantadine, see here.

Hepatitis C Drug Pipeline

It seems like every week, companies are issuing press releases about their new hepatitis C drug candidates—protease inhibitors, polymerase inhibitors, immunomodulators, you name it and it seems like everyone and their cousin is cooking something up in their labs. And every few months you’ll see a batch of reports from scientific conferences touting new data—this week it’s Digestive Disease Week (DDW) in New Orleans, last month it was the 39th Annual Meeting of the European Association for the Study of the Liver (EASL) in Berlin. How do you keep up, and how do you make sense of it all?

If you want to hear about all the latest drug development news and data, here are three websites (in alphabetical order) that do a good job of covering the waterfront:

HCV Advocate/Hepatitis C Support Project

HIVandHepatitis.com

National AIDS Treatment Advocacy Project (NATAP)

All three sites compile news stories and conference reports, and all three let you sign up for email updates. Each is well worth checking out.

HCV Advocate also maintains a chart [PDF version] of hepatitis C treatments in clinical development (clinical = human studies; preclinical = in vitro/test tube and animal studies), last updated in February. Another chart that includes compounds in preclinical development is available here, last updated in November.

Now, as for making sense of it all….

The real IDEAL: Peg-Intron vs. Pegasys

Schering-Plough recently announced the launch of a major study pitting their pegylated interferon, Peg-Intron, against Roche’s Pegasys. The study is dubbed IDEAL, an inventive acronym for “Individualized Dosing Efficacy vs. flat dosing to Assess optimaL pegylated interferon therapy.” IDEAL will enroll 2,880 adults with hepatitis C at about 100 sites across the United States (see IDEAL web site for study locations). To be eligible for the study, you have to have hepatitis C genotype 1 (the strain most common in the U.S., but least responsive to treatment). Only people who have never been treated before will be included (see inclusion and exclusion criteria).

The study requires that you be “free from substance abuse for the past 2 years” – a more conservative criteria than those recommended in the AASLD clinical practice guidelines [PDF] and the 2002 NIH consensus statement. The study also excludes people co-infected with HIV, who generally do not respond as well overall to hepatitis C treatment.

People enrolled in the study will be randomly assigned to one of three arms, each providing 48 weeks of treatment (study drugs provided for free):

Arm 1: high-dose Peg-Intron (1.5 μg/kg/week) with weight-based ribavirin (Schering’s Rebetol, at 800-1,400 mg/day) – 960 study participants

Arm 2: low-dose Peg-Intron (1.0 μg/kg/week) with weight-based ribavirin (Schering’s Rebetol, at 800-1,400 mg/day) – 960 study participants

Arm 3: Pegasys (180 μg/week) with weight-based ribavirin (Roche’s Copegus, at 1,000-1,200 mg/day) – 960 study participants

The study is designed to see whether there are differences between the three arms in the proportion of study participants achieving a sustained virologic response (SVR), defined as an undetectable hepatitis C viral load 6 months after the end of treatment.

So — assuming that you’re clean and sober and HIV-negative — should you rush off to sign up for this trial? First, it’s worth understanding the reasons for the three-arm design.

New Jersey Prisoner Files Lawsuit on Hepatitis C Care

Jose Lopez, a New Jersey inmate living with hepatitis C, filed a federal lawsuit against the New Jersey Corrections Department and its medical contractor, Correctional Medical Services Inc (CMS). According to the lawsuit, Mr. Lopez tested positive for hepatitis C in prison in 1992, but was only informed of his status in 2002. He subsequently received hepatitis C treatment but did not respond to therapy. Medical records show that he now has signs of cirrhosis. According to his attorney, Mark B. Frost, "His health is deteriorating, and medical treatment has not been helpful," Frost said in the interview. "There's no way for him to get better." Frost alleges that “[t]he conduct of prison officials and medical providers was outrageous. Not to inform Mr. Lopez of a life-threatening disease is tantamount to watching a person having a heart attack and sit idly by." (Quoted in an article in the Philadelphia Inquirer, “State inmate files U.S. suit over lack of hepatitis care,” Mark Fazlollah, 5/13/04)

This case is not unusual. The prison system has historically refused or restricted access to hepatitis C treatment to incarcerated persons, due primarily to its expense. The cost of treatment comes out of limited prison health budgets. Prison health care is increasingly contracted out to private, for-profit companies, increasing the incentive to save money by refusing to provide treatment (see Prison HMOs and Inmate Health Care by Liz Highleyman in the Nov/Dec 2003 issue [PDF file] of Hepatitis C Awareness News, the newsletter of the National Hepatitis C Prison Coalition). In turn, prisons have been reluctant to provide testing for hepatitis C, since that would spark further demand for treatment.

Surveys show that between 16% and 41% of people incarcerated in state and federal prisons have hepatitis C. Rates are higher among incarcerated women. In any given year, one-third of all people with hepatitis C in the United States spend time in a correctional facility. These statistics are a direct result of the war on drugs and high rates of incarceration of drug users.