U.S. Food & Drug Administration Acts to Bolster Supply of Critically Needed Cancer Drugs Including Doxil

The U.S. Food and Drug Administration today announced a series of steps to (i) increase the supply of critically needed cancer drugs, and (ii) build upon President Obama’s Executive Order to help prevent future drug shortages.  To alleviate the Doxil cancer drug shortage, the FDA approved  the temporary importation of a replacement drug named “Lipodox” (doxorubicin hydrochloride liposome injection), with the expectation of  ending the U.S. shortage and fully meeting patient needs in the coming weeks. Doxil is an important weapon in the fight against recurrent ovarian cancer.

The U.S. Food and Drug Administration today announced a series of steps designed to increase the supply of critically needed cancer drugs, and build upon President Obama’s Executive Order, dated October 31, 2011 (No. 13588), in an attempt to prevent future drug shortages.

Margaret Hamburg, M.D., Commissioner, U.S. Food & Drug Administration

“A drug shortage can be a frightening prospect for patients and President Obama made it clear that preventing these shortages from happening is a top priority of his administration,” said FDA Commissioner Margaret A. Hamburg, M.D. “Through the collaborative work of the FDA, industry, and other stakeholders, patients and families waiting for these products or anxious about their availability should now be able to get the medication they need.”

In response to the critical shortage of the cancer drug Doxil (doxorubicin hydrochloride liposome injection) and rapidly declining supplies of methotrexate, the FDA took proactive steps needed to increase available supply for patients in the U.S.

For Doxil, there will be temporary importation of a replacement drug named “LipoDox” (doxorubicin hydrochloride liposome injection), which is expected to end the shortage and fully meet patient needs in the coming weeks.

For methotrexate, in addition to already announced actions, the FDA approved a new manufacturer of preservative-free formulation of methotrexate that is expected to further bolster supply and help avert a shortage of this lifesaving medicine. the FDA expedited review of the application to help address this potential shortage.

In response to President Obama’s Executive Order #13588 regarding prescription drug shortages, the FDA today issued draft guidance to industry which provides detailed requirements for both mandatory and voluntary notifications to the FDA of issues that could result in a drug shortage or supply disruption. Because of President Obama’s Executive Order #13588 and the FDA’s letter to manufacturers on the same day, increased awareness of the importance of early notification has resulted in a sixfold increase in voluntary notifications by industry of potential shortages. In 2011, there were a total of 195 drug shortages prevented. Since the issuance of Presidential Executive Order #13588, the FDA has prevented 114 drug shortages.

Under the FDA’s exercise of enforcement discretion, the chemotherapeutic drug LipoDox will be imported as an alternative to Doxil. Doxil is used in multiple treatment regimens, including treatment of ovarian cancer after failure of platinum-based chemotherapy (e.g., carboplatin or cisplatin). The drug is also indicated for use in AIDS-related Kaposi’s sarcoma and multiple myeloma. The FDA anticipates that the incoming supply of LipoDox will be able to fully meet patient needs.

The FDA’s exercise of enforcement discretion for Lipodox is a temporary, limited arrangement specific to Sun Pharma Global FZE (a United Arab Emirates entity) and its authorized distributor, Caraco Pharmaceutical Laboratories Ltd. (a U.S. subsidiary of Sun Pharmaceutical Industries Ltd., a leading Indian pharmaceutical company).

Temporary importation of unapproved foreign drugs is considered in rare cases when there is a shortage of an approved drug that is critical to patients and the shortage cannot be resolved in a timely fashion with FDA-approved drugs.

When a company is identified that is willing and able to import the needed drug product, the FDA evaluates the foreign-approved drug to ensure that it is of adequate quality and that the drug does not pose significant risks for U.S. patients. Only after successful evaluation of these factors does the FDA exercise its enforcement discretion for the temporary importation of an overseas drug into the U.S. market.

Methotrexate is a drug that is needed for the treatment of many forms of cancer and other serious diseases. For example, preservative-free methotrexate is needed for the intrathecal (injection into the fluid surrounding the brain and spinal cord) treatment of children with acute lymphocytic leukemia (ALL), as well as high-dose therapy of osteosarcoma.

To alleviate the shortage of methotrexate, the FDA has successfully engaged several firms to assist in maintaining supplies to meet all patient needs. First, the FDA has prioritized the review and approval of a preservative-free methotrexate generic drug manufactured by APP Pharmaceuticals (APP) and expects that product to become available in March 2012 and continue indefinitely. Second, Hospira expedited release of additional methotrexate supplies, resulting in 31,000 vials of new product – enough for more than one month’s worth of demand – being shipped to hundreds of U.S. hospitals and treatment centers today. The FDA is actively working with other manufacturers of methotrexate who have also stepped up to increase drug production for the purpose of meeting patient needs, including Mylan and Sandoz Pharmaceuticals.

APP’s application for preservative-free methotrexate is a supplement to its already approved generic drug application that the firm had previously discontinued. When the FDA became aware of potential problems with the supply of the drug (attributable to the voluntary plant closing of the largest methotrexate manufacturer, Ben Venue Laboratories), the agency reached out to other firms to see how the FDA could assist to meet the shortfall.

Prior to the approval of APP’s application, and the subsequent Ben Venue Laboratories’ voluntary shutdown, the FDA worked with Ben Venue on release of already manufactured preservative-free methotrexate, following its confirmation of the safety of remaining drug inventory. This supply is available already and will provide emergency supplies as the other firms also work to increase production of methotrexate in response to requests by the FDA and the public.

On October 31, 2011, the Obama Administration also announced its support for bipartisan legislation that would (i) require all prescription drug shortages to be reported to the FDA, and (ii) give the FDA new authority to enforce these requirements. While additional manufacturing capacity is necessary to fully address the drug shortage problem, additional early notification to the FDA can have a significant, positive impact on addressing the incidence and duration of drug shortages.

For more FDA information relating to the U.S. drug shortage, please click on the topics listed below:

Drug Shortages

Drug Shortage Guidance (“Guidance for Industry — Notification to FDA of Issues that May Result in a Prescription Drug or Biological Product Shortage – Draft Guidance,” dated February 2012)

Labeling for Doxil (doxorubicin hydrochloride liposome injection)

Letter from Sun Pharma Global FZE to healthcare professionals regarding doxorubicin, dated January 27, 2012.

FDA letter to Industry regarding drug shortage, dated October 31, 2011.

Labeling for methotrexate

Consumer Inquiries: 888-INFO-FDA

About the U.S. Food & Drug Administration (FDA)

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The FDA is also responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

Source: FDA acts to bolster supply of critically needed cancer drugs, FDA News Release, U.S. Food & Drug Administration, February 21, 2012.

FDA Revokes Approval of Avastin Use For Metastatic Breast Cancer; Major U.S. Ovarian Cancer Advocacy Organization Concerned

Today, the U.S. Food and Drug Administration (FDA) Commissioner Hamburg revoked approval of Avastin for treatment of metastatic breast cancer in the U.S. The decision does not impact Avastin’s availability for its approved uses for other cancer types in the U.S. A major U.S. ovarian cancer advocacy organization is concerned that the FDA decision will make it more difficult for ovarian cancer patients to gain access to Avastin.

FDA Revocation of Avastin Approval For Metastatic Breast Cancer

FDA Commissioner Margaret A. Hamburg, M.D., said today she is revoking the agency’s approval of the breast cancer indication for Avastin® (bevacizumab) after concluding that the drug has not been shown to be safe and effective for that use.

Avastin will still remain on the market as an approved treatment for certain types of colon, lung, kidney and brain cancer (glioblastoma multiforme).

“This was a difficult decision. FDA recognizes how hard it is for patients and their families to cope with metastatic breast cancer and how great a need there is for more effective treatments. But patients must have confidence that the drugs they take are both safe and effective for their intended use,” Dr. Hamburg said. “After reviewing the available studies it is clear that women who take Avastin for metastatic breast cancer risk potentially life-threatening side effects without proof that the use of Avastin will provide a benefit, in terms of delay in tumor growth, that would justify those risks. Nor is there evidence that use of Avastin will either help them live longer or improve their quality of life.”

Avastin’s risks include severe high blood pressure; bleeding and hemorrhaging; heart attack or heart failure; and the development of perforations in different parts of the body such as the nose, stomach, and intestines.

Today’s decision, outlined in Dr. Hamburg’s 69-page opinion, involves Avastin used in combination with the cancer drug paclitaxel (Taxol) for those patients who have not been treated with chemotherapy for their form of metastatic breast cancer known as “HER-2 negative.” This indication must now be removed from Avastin’s product labeling.

Dr. Hamburg’s decision is based on an extensive record, which includes thousands of pages submitted to a public docket, data from several clinical trials, and the record from a two-day hearing held in June, 2011.

Avastin was approved for metastatic breast cancer in February 2008 under the FDA’s accelerated approval program, which allows a drug to be approved based on data that are not sufficiently complete to permit full approval. The accelerated approval program provides earlier patient access to promising new drugs to treat serious or life-threatening conditions while confirmatory clinical trials are conducted. If the clinical trials do not justify the continued approval of the drug or a specific drug indication, the agency may revoke its approval. In this case, the accelerated approval was based on promising results from one study that suggested that the drug could provide a meaningful increase in the amount of time from when treatment is started until the tumor grows or the death of the patient.

After the accelerated approval of Avastin for breast cancer, the drug’s sponsor, Genentech (a member of the Roche Group) completed two additional clinical trials and submitted the data from those studies to the FDA. These data showed only a small effect on tumor growth without evidence that patients lived any longer or had a better quality of life compared to taking standard chemotherapy alone – not enough to outweigh the risk of taking the drug.

The FDA’s Center for Drug Evaluation and Research (CDER), which is responsible for the approval of this drug, ultimately concluded that the results of these additional studies did not justify continued approval and notified Genentech that it was proposing to withdraw approval of the indication.

Genentech did not agree with CDER’s evaluation of the data and, following the procedures set out in FDA regulations, requested a hearing on CDER’s withdrawal proposal, with a decision to be made by the FDA Commissioner. That two-day hearing, which took place June 28-29, 2011, included recommendations from the FDA’s Oncologic Drugs Advisory Committee (ODAC), voting 6-0 in favor of withdrawing approval of Avastin’s breast cancer indication. After the hearing, the public docket remained open until August 4, 2011. In an earlier meeting of the ODAC, that committee had voted 12-1 in favor of the removal of the breast cancer indication from the Avastin label.

“FDA is committed to working with sponsors to bring promising cancer drugs to market as quickly as possible using tools like accelerated approval,” Dr. Hamburg said. “I encourage Genentech to consider additional studies to identify if there are select subgroups of women suffering from breast cancer who might benefit from this drug.”

Genentech Response

In a press release issued earlier today, Genentech’s Hal Barron, M.D., chief medical officer and head, Global Product Development, stated:

“We are disappointed with the outcome. We remain committed to the many women with this incurable disease and will continue to provide help through our patient support programs to those who may be facing obstacles to receiving their treatment in the United States. Despite today’s action, we will start a new Phase III study of Avastin in combination with paclitaxel in previously untreated metastatic breast cancer and will evaluate a potential biomarker that may help identify which people might derive a more substantial benefit from Avastin.”

Genentech emphasizes the following points in its press release:

  • The FDA Commissioner revoked approval of Avastin for treatment of metastatic breast cancer in the U.S.
  • The FDA’s action concludes its review of Avastin’s use for metastatic breast cancer.
  • The FDA decision does not impact Avastin’s approved uses for other cancer types in the U.S. or other countries.
  • The FDA decision does not impact the approval of Avastin for metastatic breast cancer in more than 80 foreign countries.
  • Roche will initiate a new clinical trial of Avastin plus paclitaxel in metastatic breast cancer.
  • Genentech will issue a letter to healthcare providers and will also provide them with a letter to distribute to their patients. Both letters will be made available on Genentech’s website.
  • Patients with questions or concerns about insurance coverage, or doctors with questions about reimbursement, can call Genentech’s Access Solutions Group at (866)-4- ACCESS.
  • Doctors with questions about Avastin can call Genentech’s Medical Communications group at (800) 821-8590.
  • The FDA’s action does not impact ongoing clinical trials with Avastin in breast cancer. For more information, please call Genentech’s Trial Information Support Line at (888) 662-6728 or visit clinicaltrials.gov.

Major U.S. Ovarian Cancer Advocacy Organization Concerned About Future Impact of FDA Decision

Karen Orloff Kaplan, MSW, MPH, ScD, Chief Executive Officer, Ovarian Cancer National Alliance

Karen Orloff Kaplan, MSW, MPH, ScD, the Chief Executive Officer for the Ovarian Cancer National Alliance (OCNA), expressed concern that the removal of metastatic breast cancer from the Avastin label could negatively affect women with ovarian cancer, for whom the drug is used “off-label.”  OCNA is one of the most influential advocates for women with ovarian cancer in the United States.

Dr. Kaplan stated:

“Results from three Phase III clinical studies show that Avastin is beneficial for some women with ovarian cancer. We are deeply concerned that the Food and Drug Administration’s decision regarding metastatic breast cancer will make it difficult for women with ovarian cancer to access Avastin, and that patients could be denied insurance coverage for this treatment. The Ovarian Cancer National Alliance will continue our work to ensure that drugs that are useful and medically appropriate are available to women with this disease.”

In the FDA report accompanying her decision, Commissioner Hamburg cited a lack of evidence that Avastin improved overall survival for women with metastatic breast cancer in its decision. “Given how difficult it is to measure overall survival in ovarian cancer clinical trials, we are concerned that today’s ruling may set an unfortunate precedent,” said Dr. Kaplan.

Currently, various national cancer treatment guidelines, such as the National Comprehensive Cancer Network (NCCN) Compendium™, include Avastin as a treatment for ovarian cancer. Despite that fact, the FDA’s decision could prompt a reexamination of industry treatment guidelines by various groups, including the NCCN. The NCCN  is a nonprofit alliance which consists of 21 leading U.S. cancer centers.

Specifically, OCNA is concerned that the FDA Avastin label change, mandated by today’s FDA decision, will lead to restrictions by third party payers, including the U.S. Medicare federal insurance program, who generally reimburse for Avastin when a woman’s cancer has returned. OCNA’s concern may be warranted because Reuters reported earlier today that some healthcare insurers have already started pulling back on Avastin reimbursement coverage for breast cancer.

As of now, according to Reuters, Medicare will continue to pay for Avastin used in the treatment of breast cancer, despite  the FDA’s revocation decision. “Medicare will continue to cover Avastin,” said Don McLeod, a spokesman for the Centers for Medicare and Medicaid Services (CMS). “CMS will monitor the issue and evaluate coverage options as a result of action by the FDA but has no immediate plans to change coverage policies.” The CMS statement may mitigate concerns that patients using the drug would lose critical drug reimbursement insurance coverage in the future.

Sources:

Addtional Information:

FDA Issues Final Rules to Help Patients Gain Access to Investigational Drugs

The U.S. Food and Drug Administration (FDA) published two rules [on August 12, 2009] …that seek to clarify the methods available to seriously ill patients interested in gaining access to investigational drugs and biologics when they are not eligible to participate in a clinical trial and don’t have other satisfactory treatment options.

U.S. Food & Drug Administration

U.S. Food & Drug Administration

The U.S. Food and Drug Administration (FDA) published two rules [on August 12, 2009] …that seek to clarify the methods available to seriously ill

Margaret Hamburg, M.D., Comissioner of Food & Drugs, U.S. Food & Drug Administration

Margaret A. Hamburg, M.D., Commissioner of Food & Drugs, U.S. Food & Drug Administration

patients interested in gaining access to investigational drugs and biologics when they are not eligible to participate in a clinical trial and don’t have other satisfactory treatment options.

To support the effort to help these patients, the agency also is launching a new Web site where patients and their health care professionals can learn about options for investigational drugs. In general, these options include being treated with a drug that has been approved by FDA, being given an investigational drug as part of a clinical trial, or obtaining access to an investigational drug outside of a clinical trial.

The new rule, “Expanded Access to Investigational Drugs for Treatment Use,” makes investigational drugs more widely available to patients by clarifying procedures and standards. The other rule, “Charging for Investigational Drugs Under an Investigational New Drug Application,” clarifies the specific circumstances and the types of costs for which a manufacturer can charge patients for an investigational drug when used as part of a clinical trial or when used outside the scope of a clinical trial.

“With these initiatives, patients will have the information they need to help them decide whether to seek investigational products,” said Margaret A. Hamburg, M.D., Commissioner of Food and Drugs. “For patients seeking expanded access to investigational drugs and biologics, the new rules make the process easier to understand.”

Clinical trials are studies of drugs and biologics that are still in development and have not yet been approved by the FDA. Many patients enroll in clinical trials to gain access to investigational therapies and contribute to finding out how well an investigational therapy works, and how safe it is for patients. Obtaining a drug or biologic under an expanded access program may be an option for some patients who are not able to enroll in clinical trials.

The FDA has allowed expanded access to experimental drugs and biologics since the 1970s. That access has allowed tens of thousands of patients with HIV/AIDS, cancer, and other conditions to receive promising therapies when no approved alternative is available.

“The final rules balance access to promising new therapies against the need to protect patient safety and seek to ensure that expanded access does not discourage participation in clinical trials or otherwise interfere with the drug development process,” said Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research. “Clinical trials are the most important part of the drug development process in determining whether new drugs are safe and effective, and how to best use them.”

Source: FDA Issues Final Rules to Help Patients Gain Access to Investigational Drugs, FDA News Release, News & Events, U.S. Food & Drug Administration, 12 Aug. 09.

Additional Information: