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 of Drugs for Life Threatening Illnesses- An Overview

UPDATED NOVEMBER 21, 2011

If you have followed the news and this blog, you know that there is a nationwide shortage of Doxil, a chemotherapy drug used to treat recurrent ovarian cancer, multiple myeloma and Kaposi’s sarcoma.   News of the shortage first surfaced in July 2011  with new supplies expected in mid or late August, 2011.  However, that prediction from the drug distributor turned out to be wholly inaccurate.

The drug is owned and distributed by Janssen Products, LP, a Johnson & Johnson company.  Ben Venue Laboratories in Bedford, Ohio, the manufacturing arm of Bedford Laboratories and a unit of Boehringer Ingelheim GmbH of Germany, manufactures Doxil under contract to Janssen.

To explain the Doxil shortage, Ben Venue’s representative said 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." However, Ben Venue Labs has decided to exit the Doxil business and other contract manufacturing to focus more on its business as Bedford Laboratories, a producer of generic injectables, and avoid all the problems that have caused bans from Canada and Europe of Ben Venue products.  In the meantime, as Bedford Laboratories, the company has discontinued manufacture of mainline cancer drugs cisplatin and carboplatin and has significant shortages of Taxol. It appears to focus on commonly prescribed 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.

As of today, there is no indication that the Doxil shortage will end any time soon. Janssen's president, a cancer survivor himself, sympathizes with those affected by having treatment plans interrupted or changed.  However, in 2010, Janssen chose to rely on one manufacturer to produce Doxil, even though in the past, it had a second manufacturer abroad, Schering Plough. Doxil also has no generic competition because it effectively still has patent protection in the US until 2014.  Doxil's patent expired in 2009 but J&J/Janssen still has the monopoly under the Orphan Drug Act as a reward for acquiring the company which produced a drug for a rare condition-one affecting fewer than 200,000 people.

In fact, on November 19, 2011, the Wall Street Journal reported that Ben Venue had stopped manufacturing drugs, including Doxil, altogether:

A troubled contract manufacturer, whose problems caused a shortage of Johnson & Johnson's (JNJ) cancer drug Doxil, has suspended manufacturing and distribution of products from its Ohio plant, saying routine preventive maintenance and other required actions were overdue. . . . Before its decision to halt production, Ben Venue had strained to balance factory remediation efforts with the need to continue supplying critical drugs, a newly released document shows.

See also here.

Janssen knew or should have known that Ben Venue had a history of manufacturing and quality control problems that would lead shortages and thus should not have been the sole manufacturer in the world of Doxil (called Caelyx in other parts of the world.) The FDA recently issued an unusually lengthy 483 report showing complaints about quality control since 2006 and 48 GMP (good manufacturing practices) violations.  Public records of these FDA inspections and an earlier 483  report have been available since  at least 2007.  The European Medicines Agency also inspected Ben Venue and found quality control issues.

Not only is Doxil currently unavailable for most people who need it, the mainstay chemotherapies for ovarian cancer--cisplatin, carboplatin and taxol (placitaxel) are also in shortage.  Cervical cancer and endometrial cancer are also disproportionately affected by these shortages.  The common drugs used to treat cervical cancer,  cisplatin, carboplatin, taxol (placitaxel) and fluorouracil, 5-FU, are all in shortage.  Fluorouracil is also used to treat colorectal cancer and pancreatic cancer, which are obviously gender neutral cancers.  And do not forget that Taxol is one of the mainstay treatments for breast cancer which is diagnosed in about 230,000 women per year in the U.S. with 2.5 million survivors. Endometrial cancer’s mainline chemo treatments are carboplatin, Taxol, doxorubicin and cisplatin, all of which are in short supply.  Unfortunately, another cancer whose treatment is seriously affected is testicular cancer, for which 3 of 4 mainline chemo treatments (Bleomycin, Etoposide, and Cisplatin) have shortages.  The following generic drug companies have mainline chemo shortages:

Taxol-- APP, Bedford, Hospira, Sandoz and Teva
Carboplatin-- APP, Bedford, Sandoz and Teva.
Cisplatin-- APP, Bedford, BMS and Teva.
Fluorouracil--APP, Teva, and Mylan
Bleomycin—APP, Bristol-Myers, Hospira and Teva (Bedford ceased manufacture)
Etoposide—APP, Bedford, Teva

Drug shortages, which according to the American Society of Health-System Pharmacists (ASHP) as of today exceed 200 drugs, (the FDA, who receives voluntary reports of shortages from drug companies, lists over 170) 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 us and most likely in an emergency setting when you rely on hospitals and medical personnel having the medications necessary to keep you alive. 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".

A hearing was held on Friday September 23, 2011 in the House Energy and Commerce subcommittee on Health about the drug shortages.

FACTS FROM THE HEARING (as reported by Ovarian Cancer National Alliance):
• 54 percent of shortages are due to quality control issues
• 21 percent of shortages are due to delays in manufacturing or capacity issues
• 99 percent of hospitals report experiencing one or more drug shortage in the first six months of 2011
• 66 percent of hospitals report an oncology drug shortage
• In an April 2011 survey, more than 90 percent of anesthesiologists reported at least one drug shortage at the time of the survey and 98 percent reported a shortage at some time during the past year
• The shortages have cost hospitals $415 million in drug and labor costs

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?

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.