Saturday, November 19, 2011

Shortages of Drugs for Life Threatening Illnesses- An Overview


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

Monday, November 14, 2011

Money, Money, Money, Money . . . Money- More on the Doxil Shortage

"Some people got to have it."

J&J company, Janssen Products, LP, posted an update last week(on 11/9/11) about the Doxil shortage.  Unfortunately there is no indication that the shortage will end any time soon.  Janssen's president, as a cancer survivor himself, sympathizes with those of us affected by having our treatment plans interrupted or,  in my case, changed.  But, we are s#!t out of luck because Janssen chose to rely on one manufacturer to produce a drug which 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).

According to Janssen,  this shortage has nothing to do with profit.  Here is Janssen's explanation:

Supply Management and Reason for the Current Shortage of DOXIL®

It is our practice to provide early warning of any shortage in supply of our medications so that prescribers, pharmacists and authorized distributors have as much lead time as possible to plan and source alternative treatment options where it may be appropriate. We alerted the U.S. Food and Drug Administration (FDA) and the healthcare community in June when we first determined that DOXIL® might be in short supply for a few weeks. When we learned that the shortage would be longer term, we quickly alerted healthcare professionals and directed them not to start new patients on DOXIL®. We have since continued to provide regular updates on the status of DOXIL® supply. 
The current short supply situation has been caused, in part, by unplanned downtime due to equipment failures at our independent specialty manufacturer. Some have challenged us, asking if our DOXIL® shortage is financially motivated in any way. We appreciate this opportunity to tell you that this is absolutely not the case. 
We are working closely with this supplier to restore uninterrupted access to DOXIL® as quickly as possible. Until that time, we expect product supply to remain intermittent over the next several months as this manufacturer works to return production capacity to the levels necessary to supply all patients in need. DOXIL® is complex to manufacture -- consisting of multi-step processes that require significant production times – which may add to the time it takes to bring us back up to full supply. (Italics added)
I still do not understand how equipment failures would lead to such a long time to restore production.  I am inclined to believe Ben Venue's original explanation to the WSJ in July  2011 that Ben Venue had made decisions to "prioritize" drug production  in response to a loss of production capacity and other production problems at their facility.  To me, this statement makes clear that Ben Venue decided to focus on manufacturing other more profitable drugs than Doxil when production problems arose, which is supported by Ben Venue's decision at about the same time to get out of the Doxil manufacturing business.  Given that  Janssen  had only this one manufacturer and no contingency plan when production stopped, I can only conclude that Janssen did not consider this drug sufficiently important (i.e. profitable), notwithstanding their protestations to the contrary and their orphan drug exclusivity status.

A recent article in the New England Journal of Medicine (The Shortage of Essential Chemotherapy Drugs in the United States,Mandy L. Gatesman, Pharm.D., and Thomas J. Smith, M.D.N Engl J Med 2011; 365:1653-1655 November 3, 2011)  also agrees that the drug shortages are first and foremost caused by profit motive:
The main cause of drug shortages is economic. If manufacturers don't make enough profit, they won't make generic drugs. There have been some manufacturing problems, but manufacturers are not required to report any reasons or timetable for discontinuing a product. Contamination and shortages of raw materials probably account for less than 10% of the shortages.
Janssen still has not told us much of anything about why the Doxil shortage happened and when it will be fixed.  To me, that is completely irresponsible and lamentable.  However, until the health care system in this country is not solely governed by the profit motive, we can expect no other result.

Wednesday, November 2, 2011

Halloween 3.0

My son and grandson are visiting for a while and staying with us.  I love having them here even with the  chaos that inevitably comes from adding more people, including an active child, to the household.  My 6 year old grandson joined me last night to watch an episode of Star Trek TNG which I forced my children to watch when they were growing up during the initial broadcasts.  And my grandson dressed up as a Teenage Mutant Ninja Turtle for Halloween just like his Dad did over 20 years ago.  Ironically I have the old costume from my son's childhood but it got put into deep storage so my grandson got his choice of a new costume.

This year on Halloween I did not participate in handing out candy or going trick or treating with the grand-boy.  Instead I stayed in my room reading and playing on the computer while others took over these Halloween tasks that I have done for so many years.  My son carved a pumpkin which I saw in the kitchen before I went to "hide" in the bedroom.  It looked fantastic and much better than anything I ever did when he was a child.  I could not find our regular tea candles so, after grousing a while, I gave him a more expensive aromatherapy candle to put in the pumpkin to go outside.  A few minutes later I saw the results of his artistry as the candle lit through the etchings on the pumpkin.  However, I did not see it in person.  Instead I saw a picture of it on Facebook.  In addition to clicking "like" I yelled down to my son that the pumpkin looked great!   Are we a modern family or what?

Paradise Pumpkin 10/31/11