Doxil, who is being affected?
The ongoing shortage of Doxil is impacting both patient treatment and the progression of clinical trials, meaning its effects are not only being felt now, but drug development for future treatments is also being impacted.
In the United States, Doxil is licensed to treat ovarian cancer, AIDS-related Kaposi's sarcoma, and multiple myeloma. Undoubtedly the shortage of Doxil is having a resounding impact on the treatment of all these diseases. In ovarian cancer, Doxil can be used to treat patients whose disease has recurred after initial therapy. In the current Doxil shortage, oncologists have to turn to therapeutic options, which may not typically be their first choice for patients.
The impact this is having on patient quality of life is almost impossible to tell, but certainly oncologists must be feeling the strain of not being able to prescribe their therapy of choice. Patients are undoubtedly feeling shocked and disappointed to have either be told part-way through treatment that Doxil is no longer available, or to realize they are receiving a different agent because Doxil is not available, rather than out of physician choice.
Doxil's supply shortages are also beginning to impact clinical trials for ovarian cancer. Because Doxil is frequently used to treat the disease, several clinical trials of emerging therapies for ovarian cancer use Doxil as a comparator. Furthermore, an emerging drug may be tested in combination with Doxil, with the aim of adding to its benefit. This issue has affected Endocyte, who are developing the emerging therapy EC145 for the treatment of recurrent, platinum-resistant ovarian cancer. EC145's pivotal Phase III trial (PROCEED) is studying the drug in combination with Doxil versus Doxil alone. Owing to the shortage in Doxil, the PROCEED trial is now on hold, and in a company presentation Endocyte confirmed that new supplies of Doxil were not being given to the trial. It's more than likely that other clinical trials utilizing Doxil are suffering a similar fate.
Doxil, what's the delay?
In June 2011, Centocor Ortho Biotech (now Janssen) issued a letter to U.S. healthcare providers detailing a shortage of the drug Doxil (pegylated liposomal doxorubicin, or PLD). This shortage was caused in part by production delays at a specialty manufacturing plant, Ben Venue Laboratories, for Doxil.
The shortage of Doxil has been far-reaching as the affected plant is the sole manufacturer of Doxil, meaning its supply difficulties have affected markets worldwide. In August 2011 in Europe (where PLD goes under the brand name Caelyx), the European Medicines Agency issued a letter detailing the likely shortage in supply of the agent due to the manufacturing problems in the United States. The Ministry of Health, Labor, and Welfare in Japan issued an announcement in November 2011 that no new patients should start on Doxil therapy, as there would be a shortage of the agent in 2012.
The story continues. Since these initial announcements of the PLD shortage, further announcements have been made, and the delay to the expected date for new Doxil supplies has pushed further away. Few shipments of the drug have been dispatched since mid-2011, and as a result the Creating Awareness and Reinforcing Education Support (CARES) physician access program has been set up in the United States. The CARES program will deliver PLD to physicians as it becomes available, and is also in place to prevent supplies of the drug being hoarded.
In a further twist, November 2011 saw Ben Venue Laboratories announcing that it had temporarily suspend manufacture and distribution of products made at the plant (including Doxil, but also affecting a number of other chemotherapies) in order to complete site-wide assessments after it found that maintenance and requalification was overdue for some of its manufacturing equipment. In December 2011 Ben Venue Laboratories did not anticipate any Doxil from the manufacturing plant would reach physicians until the end of 2012. Janssen have released statements confirming that they continue to investigate alternative short-term solutions to create a reliable supply of PLD, and that in the long-term they will transition to an alternative supplier (following news that Ben Venue Laboratories will transition away from contract manufacturing services).