We got lucky

As they say, sometimes the bear gets you but sometimes, if you are very lucky, you get the bear!  Well, I am very pleased to report that this may be one of the times our patient community can feel good about the way things turned out at the ODAC (oncology drug advisory committee) that the FDA convened on May 29th. To cut to the chase, the 13 member committee voted strongly in favor of recommending approval of Humax-CD20 (ten votes for and 3 against).  Not bad!  The next step is FDA accepting the recommendations of their own advisory committee and formally approving the drug.  I am told a decision is expected in a couple of months.  Hopefully the company will ramp up manufacture and get the drug out into the market soon after that.  With luck, we should have access to Humax-CD20 before the end of the year (Arzerra - we better start getting used to this silly trade name. I can’t believe they spent good money with focus groups etc coming up with this clunker of a name.  No accounting for taste I suppose).

Details of the meeting

I was glad the company and FDA presentations took place before I had to speak, since I got to hear their perspectives.  Thanks also to all of you who sent me links to the GSK and FDA position papers that were online before the meeting (hat tip to my very good friend Karl Schwartz of lymphomation - an outstanding information and advocacy site for NHL patients).

Based on what I heard and read ahead of time, I had to modify my comments significantly.  There were two sticking points that looked like they may de-rail the approval process. Frankly, for a while there I was getting a little worried about which way this sucker was going to go down.

First, the committee saw big distinction between patients who were “double refractory” ( “DR“, formally refractory to both fludarabine and Campath) and those who were refractory to fludarabine and for whom Campath was contra-indicated because of bulky lymph nodes (“BFR” - bulky, fludarabine refractory).  This meant the number of “eligible” patients in the study got cut in half, only the double refractory patients being considered appropriate for judging the outcome of the study.

I thought this was a bunch of bs - if you will pardon my french.  There is almost universal consensus among physicians that Campath does not work on bulky nodes, that patients with nodes larger than 5 cm get little benefit from Campath therapy.   The FDA argued that because their earlier approval of Campath did not exclude bulky disease,  we cannot assume bulky disease is contra-indication for Campath therapy and therefore these two groups of patients were not the same.  Talk about covering their earlier mistake by making the same mistake all over again!

Proof of the pudding, the Humax-CD20 trial results for the DR and the BFR groups were almost identical! One of the FDA members argued that a formal trial has to be done to prove that patients with bulky disease do not respond sufficiently to Campath.  When it was my turn to speak I wished him good luck in getting such a trial going.  First, it would be close to unethical (I was being kind - it would be downright unethical) recruiting patients for a trial just to prove it will not work.   Second, patients are a lot smarter these days, we do read about this stuff more than we used to and we know more about what is likely to work and what is going to be a waste of time. I would be willing to bet him dollars to donuts that savvy patients would vote with their feet, stay away in droves from such a trial.  Talk about bureaucratic hair splitting getting ahead of commonsense! 

The second sticking point had to do with use of CT scans.  At the time when the protocol of this Humax-CD20 trial was approved, the NCI guidelines did not call for CT scans to verify response to treatment.  The company therefore did not use CT scans, instead the trial depended on physical examinations to judge the size of peripheral lymph nodes.  They had two or more physicians evaluating patients as well as external independent members looking over their shoulders to keep things kosher. More recent NCI guidelines have suggested that perhaps there is a role for CT scans in measuring adenopathy.

So this one guy on the ODAC committee (Dr. Wilson - he finally voted against approval of Humax-CD20) was all bent out of shape because the protocol did not use CT scans.  Well, duh, is that not like changing the rules half-way through the game?  But this issue has even bigger ramifications than this just one trial.  I think some of these guys are solid cancer folks, where the size of the tumor is all that matters and they are looking at patients with short fuses.  Taking a CT scan every couple of months to monitor a fast progressing solid cancer makes sense.  We are talking of changes happening fast and furious. 

This approach does not make sense in much slower paced cancers such as CLL. How would you like it if your doctor suggested CT scans every couple of months, for the next 10 or more years?  Instead of a simple blood test and a well conducted physical examination?  How would your insurance company like it? I mean, Jeez! Let’s be a tiny bit practical here.  I talk to a lot of patients about their therapy choices and possible participation in clinical trials.  There are two things that turn off patients from clinical trial participation.  The first is mandatory bone marrow biopsies and the second is multiple mandatory CT scans.  And I can’t say I blame them!

Fortunately, the CLL experts were at the meeting in full force.  Tom Kipps, Bill Wierda, Mike Keating, Susan O’Brien, Kanti Rai - to name a few.  They did a super job of bringing back the discussion to reality each time it took off on one of these wild goose chases.  Thanks guys!  You were all great.

This was supposed to be an open FDA meeting, open to the public in the name of transparency and patient friendliness. I am glad I went and I think I had a little bit of impact - every little bit helps.  But I was a little chagrined how little time or respect they gave to patient advocates.  There was very little actual desire for public participation.  I realize these are very high stakes poker games with a lot of money riding on the decisions.   Below is a graph that shows  the mega bucks Rituxan makes for its owners, a piece of the pie that Humax-CD20 wants to get.  Transparency?  You have to be born yesterday to believe that! 

I think some of the ODAC members and the FDA guys were a little taken aback by my very passionate and fierce appeal on behalf of approval of this important drug.  Would you believe it, in the last 20 years (that is right my friends, the last two gosh-darn decades), the only three drugs approved by the FDA for CLL are fludarabine, Campath and bendamustine.  Three drugs, in twenty years, for an incurable cancer.  And Humax-CD20 does a better job than anything else out there with patients that cannot use two out of these three “approved” drugs.  I swear I will pull my hair out if the FDA cannot see their way to approving Humax-CD20.

I had the pleasure of meeting Diane MacKinnon for lunch after the meeting was over.  Diane is a CLL patient, a voting member on the ODAC and I am proud to call her a good friend.  Now that the meeting is over Diane is no longer constrained by confidentiality and below are her comments on how this meeting went down.  Way to go Diane!  May you live long and prosper,  we need you on that darn ODAC committee.

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The FDA Oncological Drugs Advisory Committee voted 10-3 for accelerated approval of HUMAX-CD20 (ofatumumab or Arzerra) in Orlando on May 29th. As the patient representative I was very pleased to cast my YES vote.  It was a real pleasure to hear Chaya’s well reasoned and passionate plea during the public comment period and to have lunch with her afterwards.  Now it remains for the FDA to formally approve the drug or overrule the committee’s recommendation.

The FDA drug approval process remains a mystery to most patients and often to me as well.  Chaya asked me to recount what transpired at the meeting, which I will attempt to do.

A little background: Most drugs go to an FDA Advisory Committee for review before FDA makes a ruling.  Drugs which are clear failures or clear winners are exempt from this process.  Advisory committees are made up of appointed medical members and a statistician who may be augmented by disease specialists, a patient representative, and a consumer representative (usually an R.N. associated with some patient group).  Recruiting medical members who do not have a conflict of interest with the drug company sponsor or its competitors is no small feat.  About a month before the meeting, members are given confidential materials from the FDA containing its analysis including specific issues along with the sponsor presentation of data in the best possible light …  a lot of material to wade through. 

On May 29ththe Oncologic Drugs Advisory Committee met in Orlando FL to review the biologic license application by GlaxoSmithKline (GSK) for ofatumumab.  Based on the results of a single arm, multi-center study GSK requested accelerated approval which is granted for treatment of serious and life threatening diseases where there is an unmet medical need.  The trial(s) to support such approval must provide clear evidence of durable objective response.  This is a less stringent requirement than that required to obtain full approval.

The meeting agenda consisted of:

1. Opening remarks.

2. Presentation by the sponsor (GSK) for 45 minutes.

3. FDA presentation for 45 minutes.

4. Question period for the committee to address the presenters.

5. Open Public Hearing for up to 1 hour (there were only 2 public speakers). 

6. Up to one hour of committee questions and discussion.

7. Final vote of committee members. 

 GSK presentation:

  • 1. Introductory remarks by Dr. Debasish Roychowdhury (GSK): High level discussion of refractory CLL and the dearthof options available to such patients. List of hoops GSK has jumped through with the FDA to get to this point (key regulatory milestones). Four important decisions that resulted from discussions with FDA:
  • ORR (objective response rate) identified as acceptable surrogate endpoint likely to predict clinical benefit.
  • Double refractory patients (DR), those failing both fludarabine and alemtuzumab, have a clear unmet medical need.
  • Bulky fludarabine refractory (BFR) patients should be analyzed separately as supporting material. This decision reflects a technical distinction with no clinical difference in my opinion. (Evidently, for the FDA, the fact that most BFR patients would not respond to alemtuzumab, which has been established clinically, is not sufficient to establish an unmet medical need.)
  • Multi-arm randomized studies to confirm clinical benefit should be ongoing at time of this review.

 

  • 2. Discussion of refractory CLL by Dr. Susan O’Brien (MDA) establishing the clear medical unmet need for patients who have exhausted treatment possibilities along with the inadequacy of current salvage therapies.
  • 3. Clinical Overview of the supporting single arm clinical trial by Dr. Michael Arning (GSK). Details of study population, endpoints, protocol. Presentation of trial impressive results: ORR 58% for DR group and 47% for BFR group which is far higher than results for other salvage therapies. The duration of response was 6.5 months. Safety data, given that the patient population was heavily pre-treated and refractory, indicated the drug was relatively well tolerated with no unexpected adverse events the majority of which were moderate.
  • 4. Concluding remarks by Dr. Roychowdhury: Positive comparison of ofatumumab results with other salvage therapies plus a discussion of the clinical development plan consisting of 2 Phase II Studies which are ongoing and 2 Phase III studies which are ongoing. Unfortunately the results of these studies may not by available for up to 5 years …

 FDA presentation by Dr. Steven Lemery: 

The FDA covered some of the same ground as the sponsor presentation such as regulatory background, study overviews etc.  The issues raised by the FDA:

  • 1. Lack of objective radiographic confirmation of lymph node responses.
  • 2. Lack of reduction in lymphocyte counts for a notable subset of the patient population who had normal lymphocyte counts at baseline, i.e. no lymphocytosis. Should such people be included in approval trials?
  • 3. Variability in patient response assessments between Independent Review Committee (IRC), IRC adjudicators, trial investigators, and the FDA using the 1996 NCIWG response criteria.
  • 4. Requirement for premedication with cortisteroids (to reduce infusion reactions).

 Questions to the presenters:  Most of the questions requested clarification from GSK.

The necessity for CT scans to access lymph node response is a point of disagreement among the medical community.  Dr. Kipps (UCSD), speaking for GSK, clearly indicated that radiography is not necessary to evaluate lymph node response though there are times when it is clinically recommended.  While Dr. Wilson (NCI/NIH) on the review committee seemed to view radiography as a necessary part of clinical trials and in clinical practice.

The dosage level of premedication with cortisteroids was determined to be sufficiently low that it would not influence patient response.

It was also noted that patients with no lymphcytosis are common in a heavily treated set of patients and to not include them in a trial would be excluding an important subset.  

To this committee member it seemed that the sponsor responded well to the questions from the committee.  Which is not surprising since they had CLL experts Drs. Michael Keating, Susan O’Brien and Thomas Kipps, among others, at the ready to provide answers and explanations.

Open Public Hearing:  There were only two public speakers.  Chaya lead off with her effective plea which more or less followed the one she listed at CLLTopics.   The second speaker was difficult to hear so I cannot comment on her words.

Committee Questions and Discussion:   Much of the discussion was related to the 1996 versus the 2008 NCIWG response criteria, a discussion which was enlightening and interesting but irrelevant to the current clinical trial in question.  As one committee member put it, the 1996 standard was in effect when the clinical trial started and you cannot change the rules mid stream.  Presumably the 2008 response criteria will be advised for future CLL clinical trials, at least those related to FDA approval.

Final Vote:  As stated previously, 10 of the 13 members recommended accelerated approval of ofatumumab.   Now it is up to the FDA to make a final ruling and provide drug label specifics upon approval.