Update on Doxil Production-Possible Quality Issues?

According to the WSJ and our intrepid Doxil shortage reporter, Peter Loftus, the FDA is working with Johnson & Johnson to address the fact the Ben Venue Laboratories has completely shut down production of Doxil as of two weeks ago (November 19, 2011). However, the chances of Doxil being available anytime soon, in my opinion, are slim to none.  I would love to have J&J really explain, other than in the vaguest generalities, why it will take some time to fix this situation but all of these manufacturing processes are shielded by the assertion of confidentiality due to proprietary interests.  The FDA knows a little but they are not permitted to tell.   With something that affects life and death, the lack of transparency is astonishing and disturbing.

Now however we have something new to worry about in the limited supplies of Doxil that are available. In early November 2011  the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) as part a joint inspection with UK, French and US regulators found "significant" contamination and other quality control problems at Ben Venue.  Ben Venue "voluntarily" pulled the plug on itself.  EMA recommended the recall of three drugs: Velcade, (Millennium and J&J) used for multiple myeloma,  Vidaza  (Celgene) used to treat anemia, leukemia and bone marrow disease (MDS) and Busilvex(aka Busulfex), used to treat a form of leukemia.  The Hong Kong regulatory agency has joined in and expanded this recall.  The FDA has NOT issued any recall.

EMA did not recall Doxil (Caelyx) because Ben Venue was the sole source for manufacturing the drug. However, it did recommend that the drug not be used for new patients, an irony given that the drug is essentially not available except for the limited doses that have been distributed.  It also asked that doctors monitor patients for side effects like the deadly sepsis.  Janssen was asked to circulate a letter to that effect to physicians but nothing has yet been posted on the Doxil website as of today, December 4, 2011.  Here is what EMA said about Doxil (Caelyx):

For Caelyx, for which Ben Venue is the only manufacturing source, the CHMP considers the product to be essential only for patients already on treatment. It recommended that supplies should be available to maintain these patients on Caelyx but no new patients should be started on treatment with Caelyx until further notice. The CHMP advised that healthcare professionals should monitor treated patients intensively and immediately notify any relevant safety concerns that could be evidence of a quality assurance problem (particularly any cases of sepsis or suspected sepsis, such as acute pyrexia). The marketing authorisation holder, Janssen, has been asked to circulate a communication to healthcare professionals to reinforce these messages, requesting them to enhance monitoring and report any suspected adverse reaction or complaints that could be evidence of a quality assurance problem with the aseptic filling process. The CHMP will review the situation on a continuous basis.

For those of you who may still be taking Doxil, please check with your doctor about this warning. I suspect Janssen has not yet issued the letter even though EMA posted its findings almost two weeks ago.  Unfortunately, given that emergency injectable antibiotics are also in shortage (13% of all shortages; see page 14 of this FDA report), it may not be worth the risk to take any Doxil now.

Originally posted on my other blog on December 4, 2011

Shortages are Getting Worse-- the "New Normal"

In an odd way, I was pleased to see a report on NPR on October 3, 2011 that the drug shortages are worse than initially reported. I have been shouting "the sky is falling" since August, very concerned about the shortages affecting drugs like carboplatin, cisplatin and taxol, which are mainline treatments for several cancers (including taxol for  the ubiquitous Pinks who should join our bandwagon during Breast Cancer Month). The NPR report emphasized that there appears to be only a month's supply left of taxol at Mass General, a major U.S. hospital.

The NPR report also shone a light on the fact that these shortages, now up to 213 drugs, do not just affect people with relatively rare cancers or just people with cancer in general. The shortages include anesthetics, IV propofol used for intubation when someone cannot breathe,  injectable antibiotics such as streptomycin,and norepinephrine and labetalol  which regulate emergency cases of  low and high blood pressure respectively.  So these shortages may affect any of you (or me if I develop other health problems) and  most likely in an emergency setting when you rely on hospitals and medical personnel having the medications necessary to keep you alive.

And more important, as I pointed out in The Real Death Panels?, the shortages are leading to rationing--by the drug manufacturers like Ben Venue who are using an allocation system of only providing Doxil to a limited subset of those who already were in treatment with it, and by the hospitals or infusion centers who are deciding who more critically needs the drug.  (see my blog post Drug Shortages, Ethics and the Scramble to Stay Alive)  For example, as the 10/3/11 NPR report states, hospitals are taking from some patients to give to others.

One reason that Kevin Zakhar [a fifteen year old boy] hasn't been able to get the calcium solution he needs is that hospitals have been reserving it for patients who need it even more desperately than he does. 

Kathy Gura, a pharmacist at Children's Hospital in Boston, points to one of those patients, a tiny infant born only 23 weeks past conception, as premature as a baby can be and still survive. And he wouldn't have survived without the same kind of IV feeding that Kevin Zahkar gets.

Gura and caregivers at other hospitals say they have had to divert scarce electrolytes from other children and adults to save the lives of fragile preemies. Gura calls it "robbing Peter to pay Paul."

See also here for a discussion of one breast cancer fighter's experience with drug rationing.

And as shortages of one drug occur, other substitute drugs have increased demand which then can lead to their shortages.  No relief seems to be in sight.  As NPR says, drug shortages are "the new normal".  My reaction continues to be: how can that be possible in the United States which is known for innovation in science and medication development?  How can it be possible in any civilized society-- to leave your most vulnerable citizens without needed medications?

More about Drug Shortages- Get Out Those Scarves and Teal Arm Bands

What if the government and private donations pumped money into the development of drugs to treat a deadly cancer but suddenly when distribution of the drugs became unprofitable the companies making them stopped production.  What happens to the war on cancer then?  Should we just accept that in a capitalist economy, profits determine who lives and who dies?

I have written in other posts that it appears to me that the current chemo shortages are disproportionately affecting ovarian cancer, which is primarily an older woman's disease. I was please to find this American Cancer Society article that confirms my position. Unfortunately the article skews the discussion a bit about what has caused the shortages by also quoting  a large pharmaceutal distributor (McKesson) saying essentially it's all the FDA's fault.  The spokesperson claims that FDA's increased scrutiny on manufacturing processes and quality control have made certain drugs too low in profits to sustain production of those drugs.  The article further states,"McKesson’s Chief Medical Officer Dr. Roy Beveridge, MD, says there is no economic incentive for manufacturers to make or distribute low-priced generic drugs, and that unless the baseline system changes, shortages are going to continue."

J&J Headquarters designed by IM Pei

Ben Venue Labs, the manufacturer of Doxil, a critical treatment for recurrent ovarian cancer, for a subsidiary of Johnson & Johnson, claims that the problem is not one profit. An 9/22/11 article in courier-journal.com by Laura Ungar states:

Jason Kurtz, spokesman for the Ohio-based third-party maker, Ben Venue Laboratories, would only say “we’re facing capacity constraints” with a drug that is complex to make. He wouldn’t specify what type of constraints, but said examples of such problems include unplanned downtime because of machinery breakdowns and capital-improvement projects that limit manufacturing capacity.

However, Ben Venue Labs wants out of the Doxil business (and other contract manufacturing) to focus more on its business as Bedford Labs, a producer of generic injectables, and avoid all the problems that have caused bans from Canada and Europe of Ben Venue products.  Like the WSJ said, it is all about manufacturing priorities. In the meantime, as Bedford Labs, the company has discontinued cisplatin and carboplatin and has significant shortages in production of Taxol. It appears to focus on commonly needed and presumably more profitable drugs such as those that treat migraine (generic Imitrix), indigestion (generic Zantac) and high blood pressure (generic Inderol).

With Ben Venue moving on to greener pastures, who will J&J find to manufacture Doxil and how hard will they try? Doxil reportedly represents less than 1% of Johnson & Johnson revenues.  A few of my ovarian cancer sisters on inspire.com bulletin board noted that J&J makes a lot of money marketing to women, and in particular in women's products.   Here's one list of products that J& J sells.  Perhaps J&J needs to be reminded that they need to focus on Doxil as well, and quickly.  

In addition,  there are all the generic drug companies that have discontinued or have serious shortage in chemo drugs  ovarian cancer patients need. For Taxol, they are APP, Bedford, Hospira, Sandoz and Teva.  For carboplatin, they are APP, Bedford, Sandoz and Teva.  For cisplatin, they are APP, Bedford and Teva.  And with Bedford, now out of the ovarian chemo business for the most part, more of the market power will consolidate in the handful of generic companies left, who will continue to make "allocation decisions" of their manufacturing capacity based on profit. 


What can we do? Big Pharma would have us believe that the causes are all very complicated--increased reliance on outsourced ingredients, Medicare price controls, increased demand from all those pesky cancer patients, complicated manufacturing processes and lack of inspection capacity from the FDA.  But we all know that it boils down to making sure that Big Pharma makes maximum profit, even when lives are at stake.  This is unacceptable in a civilized society.


In my previous posts, I have encouraged people to write to Congress.  A hearing was held on Friday September 23, 2011 in the House Energy and Commerce subcommittee on Health but the human voice of the affected cancer patient was sorely missing. We can continue to try to get our government to take some action in this area which they have been loath to regulate thus far.  Or we can take our message to the streets and protest at the offices of the companies who will not manufacture the drugs we need.  We could show up at J&J corporate offices (and the generic companies too) wearing scarves and teal arm bands, with our message that we are still here, we are still fighting and they have an obligation to get us the drugs that will keep us alive.  Who's up for a road trip to New Brunswick, New Jersey?

THE REAL DEATH PANELS?

Nexium everywhere but no capacity for Doxil

Critics of health care reform warned the government would set up "death panels" if the law was enacted.  That hasn't happened, but such panels do exist, thanks to the actions of Big Pharma. Today pharmaceutical companies are choosing who will live and die when they decide not to manufacture drugs needed by cancer patients - like me - who are at risk of premature death.

There is a nationwide shortage of Doxil, a chemotherapy drug used to treat recurrent ovarian cancer, among other cancers. I learned about the shortage from my oncologist in July when he said that the best treatment for me was Doxil in combination with carboplatinum for my now recurrent ovarian cancer, but I would have to start without Doxil.  New supplies were not expected until mid or late August.

The drug is distributed by Janssen Products, LP, a Johnson & Johnson company, and manufactured by Ben Venue Laboratories in Bedford, Ohio, a unit of Boehringer Ingelheim GmbH of Germany. Ben Venue’s representative explained that the company is facing "manufacturing capacity constraints" that have held up some products, and it is working diligently to prioritize and expedite manufacturing for current orders." (WSJ 7/21/11)  I wonder if  the priorities are set because of the lower financial return Doxil brings or the fact that it is a woman's disease that Doxil mostly treats.

I learned from an online board that women around the country were scrambling to places remote from their regular treatment centers to get the precious Doxil before it runs out.  One woman said a small supply was available in Texas; another thought some could be had in Boston. It turns out that by early August, none was available in the United States.  One person has gone to Paris to finish her Doxil treatment.

Shockingly, Doxil is only one of many drugs in shortage in the United States.  Three other mainline chemotherapies for ovarian cancer, carboplatinum, cis-platin and taxol, as well as chemotherapy drugs for breast and colorectal cancer, are in short supply.  I learned from a new friend online that her clinic in Los Angeles has run out of taxol. Luckily, I get my infusions at Cedars Sinai Medical Center, which still
has a supply of these three drugs even though it does not have Doxil.

On August 18, 2011, Janssen issued its latest update on the Doxil shortage.  It announced that it had implemented its “new allocation process for a modest and limited supply of DOXIL®” and apparently all available Doxil has been distributed to certain patients whose physicians certified in writing that the patients were already on Doxil. There is now a waiting list that will be fulfilled as new supply eventually becomes available.  However, Janssen cautioned,   “As supply will remain intermittent in the coming months, Janssen Products, LP continues to recommend that no new patients be started on DOXIL®.”

So, the original announcement that Doxil would be available again by late August proved to be inaccurate.  Doxil is available again only for special limited cases, which unfortunately do not include me because I have not yet started treatment with Doxil.

According to the American Society of Health System Pharmacists, drug shortages currently affect about 200 medications in the United States, including antibiotics. The FDA reports record shortages for 2010 and projects more record shortages for 2011.  But the FDA has no power to require drug manufacturers to explain why there are shortages and effectively must beg the manufacturers to keep it informed.

The only real reason for these shortages is the economics for Big Pharma., which makes more money from new drugs, antidepressants and potency pills than generic chemotherapy drugs.  Why make drugs for which you can only charge $3.00 per dose when you can force doctors because of shortages to prescribe new medications that cost $10,000 per dose.?

This all means I could go for an indeterminate time not getting the drug that my oncologist says best increases my odds for remission.  I am starting to feel the need to scramble myself.  For this grandmother,
the “allocation system” of who gets Doxil (and possibly the other drugs with shortages used to treat ovarian cancer) has made the drug companies the real death panels.

Senator Klobucher introduced S. 296, Preserving Access to Life-Saving Medications Act, which would require manufacturers to report shortages and reasons for the shortages to the FDA. A similar bill, HR 2245, has been introduced in the House. Both bills are still in committee.

While I support this legislation, it is unfortunately merely a band-aid over a gaping wound.  Drug companies need to become more accountable for their profit driven decisions about what drugs to produce.  My fellow cancer warriors and I cannot fight the good fight if the drugs aren't even available.

Shortages, Ethics and the Scramble to Stay Alive

There is a nationwide shortage of Doxil, a chemotherapy drug used to treat recurrent ovarian cancer among other cancers. My oncologist told me two days ago when he said that I would need to start Doxil in combination with carboplatin to treat my now recurrent cancer.  New supplies are not expected until mid or late August.  The drug is distributed by Johnson & Johnson and manufactured by Ben Venue Laboratories in Bedford, Ohio, a unit of Boehringer Ingelheim GmbH of Germany. A representative of the manufacturer explained that the company is facing "manufacturing capacity constraints" that have held up some products, and it is working diligently to prioritize and expedite manufacturing for current orders." (WSJ 7/21/11)  The devil in me wonders if it is the priorities are set by the lower financial return Doxil brings or the fact that it is a woman's disease that Doxil mostly treats.

However, I also am grappling with an ethics issue.  I have joined an ovarian cancer forum on the internet where it came to my attention in one discussion that women from around the country are scrambling to get to places remote from their regular treatment centers to get the precious Doxil before it runs out.  One woman said a small supply was available in Texas; another thought some could be had in Boston.  I must say that such behavior makes me very uncomfortable.  Why should a scarce product be given to someone who shows up on a doorstep wanting it?  One of the women insisted that she was doing well and needed to finish 6 cycles even though my own oncologist said that six cycles may not be necessary for everyone (particularly someone who is "doing well").

I suppose the "battle" against cancer is like every other battle-- get in there and slug it out to get what you need and want.  I have a lot of fight in me but I find it unlikely that at this point I would fly 2000 miles to get a treatment that may not give you much more of an edge anyway.  But maybe I am still too new to this chronic cancer treatment situation.  The odds are that the rest of my life, whether it is a few years or many more, I will be going regularly for treatment.  I wonder if the more you go through treatment, the more you are desperate to make sure you get it.  If you don't, maybe the next recurrence will be your last because the cancer will have spread too far.

Is there a principled way to decide who gets the limited supplies of this cancer drug other than the slugfest for the last drops? All of us burdened with ovarian cancer need treatment to stay alive.   Is it anymore principled for me to have access to top rate health care because I have excellent health insurance whereas someone else will not get the needed drug or treatment because insurance will not pay and it is otherwise unaffordable?  Perhaps it is my diminished IQ due to learning of the recurrence of cancer, but I do not have any answers.  I just know that it makes me uncomfortable.