Carfilzomib has an important date next week.

An advisory committee to the U.S. Food and Drug Administration (FDA) will meet next Wednesday to review data about car­filz­o­mib's efficacy and safety.  The review will focus, in particular, on clinical trial results for carfilzomib ^[1] (Kyprolis ^[2]) as a treat­ment for re­lapsed and refractory multiple myeloma patients.

At the end of the meeting, the committee will vote whether or not to recommend that the FDA approve car­filz­o­mib as a new myeloma treat­ment.

A Beacon survey of financial analysts who follow the stock of Onyx Pharmaceuticals (NASDAQ:ONXX), the com­pany developing car­filz­o­mib, suggests the vote will be a nail biter.  A majority of analysts expect the committee to vote in favor of approval, but even those expecting a favorable vote think it will be close.

The FDA is not legally bound to follow its advisory committees’ recommendations regarding new drug applications, but it usually does.

Onyx Pharmaceuticals completed its application to the FDA last September to have car­filz­o­mib approved for the treat­ment of re­lapsed and refractory (resistant) multiple myeloma patients who have had at least two prior ther­a­pies (see related Beacon ^[3] news).

The FDA is required to make a decision about car­filz­o­mib’s application by July 27.

To assist it with its decision, the FDA has scheduled next week's meeting of the Oncologic Drugs Advisory Committee (ODAC).  The ODAC is the advisory committee that advises the FDA regarding cancer drugs.

The rest of this article addresses key questions regarding the upcoming ODAC meeting and the FDA's review of car­filz­o­mib's new drug application.

Is The ODAC Likely To Vote In Favor Of Carfilzomib?

Prior to each ODAC meeting, the FDA staff prepares and then distributes to the committee members a report reviewing data on the benefits and risks of the drug the committee will be reviewing during its meeting.

Accompanying the report is a question that the staff would like the ODAC to consider.  The question typically asks whether the data for the drug dem­onstrate a favorable risk/benefit profile.

At the conclusion of the ODAC meeting, the advisory committee votes on the FDA staff's question, essentially recommending whether or not the FDA should approve the drug.

The Beacon polled financial analysts who cover Onyx to see what they thought would be the out­come of the advisory committee vote.  Among the eight analysts who responded to the survey, 62 per­cent said they expect the ODAC to vote in favor of the FDA approving car­filz­o­mib.

Specifically, five of the respondents felt that a weak majority of the committee members would vote in favor of car­filz­o­mib being approved.  Two felt that a weak majority of the committee members would be opposed to approving car­filz­o­mib, and one felt that a strong majority would be opposed.  No analysts indicated that they thought a strong majority of the committee would be in favor of approval.

These expectations are more optimistic about car­filz­o­mib's chances at next week's committee meeting than pre­vi­ous reports of investor or analyst sentiment.  A June 4 ISI Group survey of more than 100 major Wall Street investors, for example, found that 72 per­cent expect car­filz­o­mib to get a negative vote at the end of next week's committee meeting.

What Is The ODAC And What Is Its Purpose?

The Oncologic Drugs Advisory Committee reviews and evaluates safety and efficacy data for marketed as well as potential new cancer drugs.  The committee then advises the FDA whether to approve the new cancer drug or to modify the approved uses of a cur­rently marketed drug.

The FDA is not legally required to follow a vote of its advisory committees.  The agency also considers the comments made during the meeting.  On occasion, the FDA decides against the advisory committee’s recommendation.

The ODAC typically is made up of 13 voting members who are experts in a variety of types of cancers as well as biostatistics and related fields.  One of these voting members can be someone selected to represent consumer interests.  The committee also can have one non-voting member appointed to represent the pharma­ceu­tical industry.

What Does The ODAC Typically Base Its Recommendation On?

Prior to the advisory committee meeting, the staff of the FDA prepares briefing in­­for­ma­tion for the advisory committee members.  Besides providing back­ground in­­for­ma­tion about the relevant disease, the document states the intended use of the drug, summarizes the efficacy and safety data, and describes any issues the FDA staff may have with the submission.

The briefing in­­for­ma­tion along with the wording of the question the FDA asks the advisory committee to vote on are important.  They provide insight into which way the FDA is leaning in regard to whether or not to approve a new drug or expand the approved use of an already marketed drug.

During an advisory committee meeting to review a new drug, the com­pany developing the drug gives several presentations.  The presentations typically explain why the drug addresses an important unmet treat­ment need, summarize pre-clinical and clinical trial results for the drug, and describe any future clinical trials that may be planned.

The FDA staff also make a presentation stating which agency employees are responsible for reviewing the drug application and what require­ments the application must meet in order to be approved.  The FDA presentation also summarizes the clinical trial results for the drug and describes any future clinical trials that are planned.  The presentation concludes with the issues the agency would like the advisory committee to discuss.

There is also a session during the meeting in which the public can address the advisory committee.  This is a time when patients, advocacy organizations, or others with an interest in whether the drug gets approved can present their comments.

What Data Will Be Presented And Discussed At Carfilzomib's ODAC Meeting?

In the case of car­filz­o­mib, the data reviewed during the ODAC meeting will be results of the drug's Phase 2 "003-A1" trial of single-agent car­filz­o­mib in re­lapsed/refractory myeloma patients.  These are the results Onyx has submitted to the FDA for review along with its application for car­filz­o­mib's approval.

Results from other clinical trials -- such as those involving car­filz­o­mib in com­bi­na­tion with Revlimid ^[4] (lena­lido­mide) and dexamethasone ^[5] (Decadron) in newly diagnosed patients -- will most likely not be discussed, since results from those trials were not part of the application Onyx submitted to the FDA.

Furthermore, a key issue during the meeting will be whether the results of the single-arm Phase 2 003-A1 trial are sufficient for the FDA to approve car­filz­o­mib.

Onyx applied to the FDA for approval of car­filz­o­mib under the so-called "accelerated approval" process.   That process permits the FDA to approve a new drug for a serious disease even if the clinical trial data for the drug are not particularly extensive.

However, by law, the FDA can only approve drugs under the accelerated approval process if the clinical trial results submitted with the new drug application are “adequate and well controlled.”  Analysts who are pessimistic about car­filz­o­mib's chances at next week's meeting believe the committee may not view the drug's Phase 2 trial data as meeting this standard.

What Does The Outcome Of The ODAC Meeting Mean?

While it is finalizing its decision in regard to car­filz­o­mib's new drug application, the FDA will consider the ODAC’s vote and other comments made during the committee's meeting.  The agency will then make its decision about the car­filz­o­mib application.

Regulatory rules require that the FDA make its decision by July 27.  The agency has the option, however, of extending this deadline if it feels it needs extra time to review car­filz­o­mib's efficacy or safety data.

There are three potential decisions that the FDA could announce when it finally concludes its review of the car­filz­o­mib new drug application.  It can approve the application, it can issue what is known as a "complete response letter," or it can turn down the application.

If the FDA feels that the clinical trial results for car­filz­o­mib sufficiently dem­onstrate a positive benefit/risk ratio for the drug's intended patient population, it will approve the drug.  That will mean that Onyx can begin marketing the drug within the United States.

If there are problems with the application, or if the FDA feels more in­­for­ma­tion is needed to decide on the application, it will issue a so-called ‘complete response letter’ to Onyx.

The complete response letter can be issued because of safety issues, failure to dem­onstrate a drug's efficacy, or manu­fac­tur­ing issues. The FDA may, for example, require Onyx to conduct addi­tional clinical studies to address the agency’s concerns. The FDA will explain its decision in the complete response letter and will give Onyx the opportunity to discuss any deficiencies in a hearing with the agency.

Onyx could then ask for a hearing, correct any deficiencies, and submit new in­­for­ma­tion, or it could withdraw car­filz­o­mib's new drug application.

A complete response letter from the FDA would, however, delay the launch of car­filz­o­mib until Onyx is able to address any questions or concerns raised by the FDA.

If the FDA comes to the conclusion that car­filz­o­mib’s risks noticeably outweigh its benefits, it will turn down the application. In that case, Onyx would have to submit a completely new drug application to be considered for approval again.

The Myeloma Beacon will con­tinue to cover the events leading up to Wednesday’s ODAC meeting and the FDA’s decision regarding the car­filz­o­mib application.

Until car­filz­o­mib receives FDA approval, the drug is available through Onyx’s expanded access pro­gram ^[6] for re­lapsed and refractory myeloma patients in the U.S. who do not have any other treat­ment options.

Carfilzomib works similarly to the existing multiple myeloma treat­ment Velcade ^[7] (bor­tez­o­mib).  Both drugs are in the class of drugs known as proteasome inhibitors.  They work by preventing the breakdown of protein in cancer cells, triggering their death.

Carfilzomib and pomalidomide ^[8] – a chemical relative of multiple myeloma drugs Revlimid (lena­lido­mide) and thalidomide ^[9] (Thalomid) – are the only drugs cur­rently under review by the FDA for potential approval as new treat­ments for myeloma.