[Federal Register Volume 75, Number 46 (Wednesday, March 10, 2010)]
[Notices]
[Pages 11189-11191]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2010-5055]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2010-N-0107]


Expanded Access to Direct-Acting Antiviral Agents for the 
Treatment of Chronic Hepatitis C Infection in Patients With Unmet 
Medical Need; Public Hearing; Request for Comments

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of public hearing; request for comments.

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SUMMARY: The Food and Drug Administration (FDA or the agency) is 
announcing a public hearing to obtain input on the scope and 
implementation of potential expanded access programs with direct-acting 
antiviral agents (DAAs) for the treatment of chronic hepatitis C (CHC) 
infection in patients with unmet medical need. This public hearing is 
being held to obtain comments from the public on eligibility criteria 
that should be used for patient enrollment in expanded access protocols 
involving DAAs and to elicit suggestions for designs of protocols for 
treatment investigational new drug applications (INDs) involving DAAs 
and other expanded access protocols. In addition, the agency would like 
public input on types of studies that should be conducted to obtain 
information on patients with unmet medical need including those with 
the greatest risk of progression of liver disease and/or the lowest 
predicted virologic response rates.

DATES: The public hearing will be held April 30, 2010, from 9 a.m. to 4 
p.m. The meeting may be extended or may end early depending on the 
level of public participation. Submit written or electronic requests 
for oral presentations and comments by April 8, 2010 (see section III 
of this document for details). Written or electronic comments will be 
accepted after the hearing until June 25, 2010 (see section V of this 
document for details).

ADDRESSES:  The public hearing will be held at the Hilton Hotel, 1750 
Rockville Pike, Rockville, MD 20852. Additional information on parking 
and public transportation may be accessed at http://

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www1.hilton.com/en--US/hi/hotel/IADMRHF-Hilton-Washington-DC-Rockville-
Hotel-Executive-Meeting-Ctr-Maryland/index.do. (FDA has verified the 
Web site addresses throughout this document, but FDA is not responsible 
for any subsequent changes to the Web sites after this document 
publishes in the Federal Register.) Submit written comments to the 
Division of Dockets Management (HFA-305), Food and Drug Administration, 
5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
    Submit electronic comments to http://www.regulations.gov. All 
comments should be identified with the docket number found in brackets 
in the heading of this document. Transcripts of the hearing will be 
available for review at the Division of Dockets Management and on the 
Internet at http://www.regulations.gov approximately 45 days after the 
hearing (see section VI of this document).

FOR FURTHER INFORMATION CONTACT: Susie Dill, Center for Drug Evaluation 
and Research, Food and Drug Administration, 10903 New Hampshire Ave., 
Bldg. 51, rm. 6183, Silver Spring, MD 20993-0002, 301-796-3437, FAX: 
301-847-8753, e-mail: [email protected].

SUPPLEMENTARY INFORMATION:

I. Background

A. CHC

    In the United States, hepatitis C virus infection causes 20 percent 
of all cases of acute viral hepatitis and from 70 to 90 percent of all 
cases of hepatocellular carcinoma. An estimated 3.2 million Americans 
are chronically infected with hepatitis C virus. CHC currently is the 
leading cause in the United States for liver transplantation, and 
modeling suggests that without effective treatment interventions, 
significant increases in CHC-associated liver morbidity and/or 
mortality could result.
    According to treatment guidelines set forth by the American 
Association for the Study of Liver Diseases, the current standard of 
care (SOC) for treatment of CHC is a pegylated interferon administered 
in combination with ribavirin (See Marc G. Ghany, et al., ``Diagnosis, 
Management, and Treatment of Hepatitis C: An Update,'' AASLD Practice 
Guidelines, (2009), available at http://www.aasld.org/practiceguidelines/Pages/SortablePracticeGuidelinesAlpha.aspx). 
Overall, following SOC treatment, sustained virologic response (SVR) 
occurs in about 40 to 45 percent of patients with viral genotype 1, 
with lower SVR rates for blacks and human immunodeficiency virus (HIV) 
co-infected patients. Pegylated interferons and ribavirin are difficult 
to tolerate and can cause significant adverse reactions that limit 
treatment in many patients or result in substantial morbidity. 
Therefore, new drugs are needed (and many are in development) to 
increase SVR rates when added to an SOC, potentially to shorten the 
duration of interferon-based regimens, or to replace components of SOC 
regimens in patients who cannot tolerate interferons or ribavirin. New 
drugs also are needed to construct regimens in patients with 
decompensated cirrhosis and in patients undergoing liver transplant. 
One option for these patients may be early access to these developing 
drug products through the ``expanded access'' regulatory scheme.

B. Authority for Expanded Access

    FDA regulations provide for treatment INDs or other access 
protocols for patients with serious or immediately life-threatening 
illnesses who have unmet medical need. See the Expanded Access to 
Investigational Drugs for Treatment Use Final Rule (Expanded Access 
Rule) (74 FR 40900, August 13, 2009). Under these regulations, a 
treatment IND, which permits patients access to unapproved drug 
products under certain circumstances prior to final agency approval, is 
possible when the following criteria have been met:
    (1) The drug is being investigated in a controlled clinical trial 
under an IND designed to support a marketing application for the 
expanded access use, or all clinical trials of the drug have been 
completed;
    (2) The sponsor is actively pursuing marketing approval of the drug 
for the expanded access use with due diligence; and
    (3) There is sufficient clinical evidence of safety and 
effectiveness to support the treatment use (21 CFR 312.320(a)).
    Alternatively, individual patient INDs and treatment access 
protocols for intermediate-sized populations are sometimes possible 
earlier in drug development (21 CFR 312.310) (IND use for treatment of 
individual patient by licensed physician)); 21 CFR 312.315 (IND use for 
treatment of patient population smaller than that typical of treatment 
IND). Proposed use under each of these three options also must meet the 
criteria set forth in 21 CFR 312.305 (requirements for all expanded 
access uses).

C. Expanded Access in CHC Context

    Some patients with CHC who have not responded to approved 
treatments and/or who are at substantial risk of liver disease 
progression may benefit from access to new therapeutic options before 
approval through the Expanded Access Rule. On the other hand, receiving 
preapproval treatment access via a treatment protocol may have 
potential risks such as adverse reactions or the development of drug or 
drug-class resistance.
    Historically, early access programs with antiretrovirals for the 
treatment of HIV allowed many people to gain access to life-saving 
drugs. For some individuals, however, early access to a drug resulted 
in what amounted to sequential monotherapy and the emergence of 
multidrug resistance. Similar to HIV treatment concerns, drug 
resistance and drug-class resistance are concerns for DAAs to treat 
CHC. Because treatment of CHC requires multiple agents to achieve 
acceptable SVR rates and to reduce the emergence of drug resistance to 
single agents or drug classes, treatment INDs that include two or more 
investigational agents or that allow for co-enrollment in several 
treatment IND programs are options to consider, particularly for 
previous null responders or for patients who cannot take interferon-
based regimens. However, the use of multiple agents in the context of a 
treatment IND adds to the complexity of the implementation and design 
of treatment IND protocols. In light of the foregoing, FDA is 
soliciting advice from the public on how treatment access protocols for 
hepatitis C DAAs may best be designed.

II. Scope of the Public Hearing

    FDA is interested in obtaining public comment on the following 
issues related to expanded access of DAAs for the treatment of CHC:
    1. What types of patients with CHC are most appropriate for 
participation in DAA expanded access for CHC with regard to disease 
stage, previous treatment, and other disease characteristics?
    2. Under what circumstances and in which populations would early 
access to a single DAA be appropriate?
    3. Under what circumstances and in which populations would early 
access to multiple DAAs be appropriate?
    4. How can pharmaceutical companies, government, academia, and 
community physicians and activists collaborate to provide for the 
treatment use of multiple new agents with the goal of maximizing 
response and reducing the emergence of drug or multidrug resistance?
    5. What potential adverse reactions should be contemplated in 
formulating DAA treatment IND use protocols?

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    6. How can pharmaceutical companies, government, academia, and 
community physicians and activists collaborate to provide for the 
treatment use of multiple new agents with the goal of maximizing 
response and reducing adverse reactions?
    7. In the course of developing DAAs for marketing, what types of 
studies should be conducted to best address unmet medical needs for 
patients with CHC including those with the greatest risk of progression 
of liver disease and/or the lowest predicted virologic response rates? 
Examples of studies that help to support clinical protocols or 
treatment use protocols in populations of unmet medical need may 
include renal and hepatic impairment studies and drug-drug interaction 
studies with antiretrovirals.

III. Attendance and/or Participation in the Public Hearing

    The public hearing is free and seating will be on a first-come, 
first-served basis. Attendees who do not wish to make an oral 
presentation do not need to register.
    If you wish to make an oral presentation during the hearing, you 
must register by submitting a written or electronic request by close of 
business on April 8, 2010, to Susie Dill (see FOR FURTHER INFORMATION 
CONTACT). You must provide your name, title, business affiliation (if 
applicable), address, telephone and fax numbers, e-mail address, and 
type of organization you represent (e.g., industry, consumer 
organization). You also should submit a brief summary of the 
presentation, including the discussion topic(s) that will be addressed 
and the approximate time requested for your presentation. We encourage 
individuals and organizations with common interests to consolidate or 
coordinate their presentations to allow adequate time for each request 
for presentation. Persons registered to make an oral presentation 
should check in before the hearing.
    Participants should submit a copy of each presentation to Susie 
Dill (see FOR FURTHER INFORMATION CONTACT). We will file the hearing 
schedule, indicating the order of presentation and the time allotted to 
each person, with the Division of Dockets Management (see ADDRESSES). 
We will mail, e-mail, or telephone the schedule to each participant 
before the hearing. In anticipation of the hearing presentations moving 
ahead of schedule, participants are encouraged to arrive early to 
ensure their designated order of presentation. Participants who are not 
present when called risk forfeiting their scheduled time.
    If you need special accommodations due to a disability, please 
contact Susie Dill (see FOR FURTHER INFORMATION CONTACT) at least 7 
days in advance.

IV. Notice of Hearing Under 21 CFR Part 15

    The Commissioner of Food and Drugs is announcing that the public 
hearing will be held in accordance with part 15 (21 CFR part 15). The 
hearing will be conducted by a presiding officer, who will be 
accompanied by FDA senior management from the Office of the 
Commissioner and the Center for Drug Evaluation and Research.
    Under Sec.  15.30(f), the hearing is informal and the rules of 
evidence do not apply. No participant may interrupt the presentation of 
another participant. Only the presiding officer and panel members may 
question any person during or at the conclusion of each presentation 
(21 CFR 15.30(e)). Public hearings under part 15 are subject to FDA's 
policy and procedures for electronic media coverage of FDA's public 
administrative proceedings (part 10 (21 CFR part 10), subpart C), (21 
CFR 10.203(a)). Under Sec.  10.205, representatives of the electronic 
media may be permitted, subject to certain limitations, to videotape, 
film, or otherwise record FDA's public administrative proceedings, 
including presentations by participants. The hearing will be 
transcribed as stipulated in Sec.  15.30(b) (see section VI of this 
document for more details). To the extent that the conditions for the 
hearing as described in this document conflict with any provisions set 
out in part 15, this notice acts as a waiver of those provisions as 
specified in Sec.  15.30(h).

V. Request for Comments

    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) written or electronic comments for consideration. 
Persons who wish to provide additional materials for consideration 
should file these materials with the Division of Dockets Management. 
You should annotate and organize your comments to identify the specific 
questions identified by the topic to which they refer. Submit a single 
copy of electronic comments or two paper copies of any mailed comments, 
except that individuals may submit one paper copy. Comments are to be 
identified with the docket number found in brackets in the heading of 
this document. Received comments may be seen in the Division of Dockets 
Management between 9 a.m. and 4 p.m., Monday through Friday.

VI. Transcripts

    Please be advised that as soon as a transcript is available, it 
will be accessible at http://www.regulations.gov. It may be viewed at 
the Division of Dockets Management (see ADDRESSES). A transcript also 
will be available in either hardcopy or on CD-ROM, after submission of 
a Freedom of Information request. Written requests are to be sent to 
the Division of Freedom of Information (HFI-35), Office of Management 
Programs, Food and Drug Administration, 5600 Fishers Lane, rm. 6-30, 
Rockville, MD 20857.

    Dated: March 2, 2010.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2010-5055 Filed 3-9-10; 8:45 am]
BILLING CODE 4160-01-S