The counterfeit drug trade has reached global proportions, and solving the problem needs a global approach.

So says an editorial in this week’s The Lancet.

While the Avastin announcement last week raised lots of concern and media attention, the issue of counterfeit drugs isn’t new. In 2009, the European Union seized 34 million fake pills in just two months, including antibiotics, cancer drugs, and sildenafil (Viagra). Counterfeit medicines are a problem for both low and high income countries and can seriously hurt patients.

In January the FDA warned healthcare providers not to buy injectable cancer medications from “direct-to-clinic” promotions or non-verified sources. Such drugs, says the FDA, put patients at risk.

The FDA tells healthcare providers who are responsible for purchasing cancer drugs for their patients:

Health care providers are reminded to obtain and use only FDA-approved injectable cancer medications purchased directly from the manufacturer or from wholesale distributors licensed in the United States.

The Lancet concludes,

The fight against counterfeit drugs must be strengthened without further delay. It needs consensus among all countries and interested parties, and requires wise and bold leadership from the World Health Organization (WHO). An indispensable goal of the campaign is ensuring the availability of genuine and affordable essential medicines in developing countries.

FDA Commissioner Margaret Hamburg announced yesterday during a teleconference that the FDA has arranged to meet critical needs for methotrexate and Doxil® (doxorubicin).

FDA has approved temporarily importing Lipodox, which has the same active ingredient — doxorubicin — and the same concentration as Doxil. There should be enough to meet needs for Doxil treatment.  FDA has inspected and approved the foreign plants that manufacture Lipodox.

APP Pharmaceuticals and Hospira both have ramped up production of methotrexate. Together they expect to be able to ship the drug immediately and have enough to meet future needs.  Methotrexate is especially needed by children with leukemia where it can produce remissions rapidly and cure most children with acute lymphoblastic leukemia (ALL).

Unfortunately, fluorouracil (5-FU) and leucovorin are still in shortage.

The FDA now has an 11 person Drug Shortage Team working to help resolve shortages. Other FDA staff are cooperating in getting information about potential inspection problems to the team or speeding up approvals for new manufacturing providers.

In addition, there has been a significant increase in voluntary reporting of potential supply problems to FDA, with a six-fold increase since the President’s Executive Order in October 2012.

As for drugs important in colorectal cancer treatment, the latest information from the American Society of Health-System Pharmacists says:

• Fluorouracil is back order by one manufacturer, who is releasing it on allocation to avoid excessive purchasing. A second company has supplies but is having difficulty meeting increased market demand. It also is allocating supplies through wholesalers. The third company has manufacturing delays and cannot estimate when the drug will be available.
• Irinotecan shortage has been resolved and is now available from all manufacturers.
• Leucovorin from Bedford Laboratories has been affected by suspension of all manufacturing at Ben Venue and cannot estimate when new supplies will be available. Teva has exhausted the supplies being imported from Europe, but expects to release more in mid-February.  APP has leucovorin on back order but expects to be able to release some in late first quarter 2012.  Spectrum has Fusilev (levoleucovorin) readily available.
• The Xeloda (capecitabine) issue has been resolved. Imported blister packs are no longer being shipped by Genentech. Tablets in bottles are available again.

During the February 21 teleconference, advocates pushed for speedy approval of legislation that would improve reporting — the Senate Preserving Access to Lifesaving Medications Act. and its companion bill in the House.

President Barack Obama signed an Executive Order yesterday addressing the drug shortage issue.

As we have reported extensively on www.FightColorectalCancer.org, the current drug shortages have impacted colorectal cancer patients who have been unable to get 5-FU, leucovorin or on occasion, irinotecan.

The Executive Order does not change the law, and it will not help patients who cannot get their drugs today, but it does reinforce the powers of the Food and Drug Administration to take steps that would ease the burden by:

• Broader reporting of when a manufacturer has stopped producing a drug that could lead to a shortage.
• Increased effort to review drug suppliers and manufacturing sites and changes. It also directs the FDA to prioritize its resources according to the burden of the shortage to the public health.
• Collaboration with the Department of Justice to address drug stockpiling and price gouging.

On hand at the signing of the Executive Order was colorectal cancer patient Jay Cuetara, who has spoken out publicly about his experience with the 5-FU shortage. Jay is featured on the White House website talking about how this issue impacts cancer patients.

For more information:

• FDA – Current Drug Shortages
• American Society of Health-Systems Pharmacists (ASHP) – Current list of drugs in short supply
• Ask your Members of Congress to support legislation that will further address this issue
• Fight Colorectal Cancer’s drug shortage FAQ

The FDA has changed the package insert for Avastin® (bevacizumab) to include information about newly identified risks for the drug including

• Loss of ovarian function (ovarian failure).
• Bone death in the jaw (osteonecrosis).
• Bleeding and additional blood clots in patients who have already had a clot in their veins while on Avastin.

Changes to the Avastin label were announced on September 30, 2011.

Ovarian Failure

Women with  stage II or III colon cancer who were getting Avastin in combination with chemotherapy during a clinical trial had reduced ovarian function compared to women who were only on chemotherapy.

Women with ovarian failure no longer had menstrual periods or had high levels of a hormone associated with menopause. Follicle stimulating hormones (FSH) blood levels were equal to or above 30.

Among 179 women in a subset of a clinical study, 84 were on FOLFOX chemotherapy alone and 95 received both FOLFOX and Avastin.

• 2% of the chemo only group had ovarian failure during treatment compared to
• 34% of those receiving chemo and Avastin.
• Only 1 in 5 of the women with ovarian failure (22%) started menstruating again and had their FSH levels fall back below 30 during post treatment visits.
• According to FDA, “Long term effects of Avastin exposure on fertility are unknown.”

Avastin Warnings and Precautions now includes:

Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin.

Avastin is not labeled to treat stage II or III colon cancer and failed to improve 3 year disease free survival in two clinical trials — NSABP C-08 and AVANT.

Osteonecrosis of the Jaw

Since Avastin has been on the market, there have been reports of lesions in patient’s mouth that don’t heal.  The jawbones literally die leading to pain and infection.  These patients were not on bisphosphonates, drugs previously linked to jaw osteonecrosis.  Bisphosphonates are used  to prevent bone loss and in some cancer treatments.

It is possible that changes in blood vessels in the jaw led to poor blood supply to the bones and their deterioration.

Osteonecrosis of the jaw has been added to the Adverse Events section of the package insert.

Venous Thromboembolic and Bleeding Events for Patients Receiving Anti-Coagulation

In clinical trials, patients who were taking Avastin, experienced a blood clot in a vein (venous thromboembolic event or VTE) and were on anticoagulant medicine to prevent more clots had higher rates of both further VTEs and bleeding than patients on chemotherapy alone.

In a trial of 1,400 patients with metastatic colorectal cancer there was a higher percentage of first VTE, subsequent VTE, and bleeding after VTE in the trial arms that contained Avastin added to chemotherapy.

• 13.5 percent of patients in the Avastin arms had an initial VTE compared to 9.6 percent of those only getting chemotherapy.

There were 116 patients who were put on anticoagulant medicine after their first blood clot — 73 on Avastin and 43 on chemotherapy alone:

• 31.5 percent had another blood clot in a vein while on Avastin compared to 25.6 percent only on chemo.
• 27.4 percent had bleeding compared to 20.9 percent of patients in the trial arms without Avastin.

This information was added to the Clinical Trial Experience section of the package insert.

What This Means for Patients

Avastin is a helpful addition to chemotherapy for people with advanced colorectal cancer. It improves survival time over chemotherapy alone in both first and second line treatment of stage IV disease.

However, patients and their doctors need to be aware of potential serious side effects as they make treatment decisions.

They also need to watch for adverse events associated with Avastin, including blood clots and osteonecrosis of the jaw.

Women who still are able to have children need to know that Avastin may affect their future fertility.

If you missed the FDA Webinar on Drug Shortages last Friday, you can

Watch a video of the entire presentation, including questions.

Download the webinar slides.

The webinar, led by Captain Valerie Jensen, R.Ph., Associate Director for the FDA’s Drug Shortage Program, discusses how the FDA responds to drug shortages and what they are doing to try to prevent shortages of medically necessary drugs.

According to Capt. Jensen, key to preventing drug shortages is manufacturers letting FDA know early when a shortage is expected.  So far in 2011, 99 shortages have been prevented by early notification.

What the FDA Can Do

With voluntary early notification, the FDA can work with manufacturers to:

• Use FDA regulatory flexibility to allow shipping of drugs that have problems that don’t affect patient safety such as misprinted labels or packaging errors.
• Allow shipping of drugs with special warnings or filters.  For instance, a drug may be safely used with a filter for particulates or crystals can be dissolved if the medication is heated.
• Speed up approvals of alternate manufacturing sites or encourage other manufacturers to ramp up production.
• Approve importation of drugs if the foreign manufacturing site meets FDA requirements for Good Manufacturing Practices.
• Approve new sources of acceptable raw materials — as they did after the Japan earthquake.

What the FDA Can NOT Do

• FDA has no authority to require manufacturers to make any drug.
• FDA can’t tell manufacturers what quantity of a drug to make or release.
• FDA can’t set prices or interfere in pricing.

Currently, only manufacturers who are the single source of a medically necessary drug are required by law to inform FDA of their intention to stop making it.  There is no penalty for not doing so.

While Capt. Jensen cannot comment on proposed legislation, she emphasized the importance of early notification of potential shortages.

A specific question from a listener to Capt. Jensen about 5-FU led to a hopeful answer. She replied that two companies are continuing to produce 5-FU and that the shortage probably is resolving based on what those companies are telling FDA.

For lists of drugs that are currently in shortage and information about when those shortages may be resolved:

• FDA Drug Shortages
• American Society of Health-Systems Pharmacists (ASHP)

To take an critically necesssary first step toward preventing future shortages, ask your Members of Congress to support the Preserving Access to Lifesaving Medications Act (H.R. 2245/Sen 296).

Drug shortages in the US are a growing crisis, members of Congress were told last Friday, September 23.  And there is no single reason why this is happening and no easy solutions to the problem.

Problems lie mostly in older generic versions of sterile injectable drugs, which are low-priced and

• complicated to manufacture
• made by a only a few companies
• manufactured in aging plants where quality is hard to maintain.

Dr. Howard Koh, Assistant Secretary of Health in the Department of Health and Human Services, told the House Energy and Commerce Subcommittee on Health that the number of drugs in shortage  had grown from 61 in 2005 to 178 in 2010 and is even larger in 2011.  Over 90 percent of drugs in shortage are medically necessary — drugs that are used to prevent or treat a serious disease for which there is no alternative.  Some are made by only one company.

According to Dr. Koh, cancer drugs made up about a third of the shortage (28%), followed by antibiotics at 13%.

In 2010 and 2011, Dr. Koh said that

• More than half of shortages (about 54 percent) were due to quality problems including drugs contaminated with tiny particles, inpurities, bacteria, or crystals.
• About 21 percent happened when there were production delays at manufacturing facilities or plants lacked the capacity to meet demand.
• Another 11 percent were caused when manufacturers stopped production, usually for business reasons.
• Problems getting raw materials, lack of components, and loss of a manufacturing site also were at the bottom of some shortages — but fewer than 10 percent.
• Finally, an increase in demand due to another manufacturer’s difficulties let the shortage spread.

Several subcommittee members asked why rules of supply and demand didn’t solve the problem, leading to higher prices and increased production to meet demand. Koh explained that the vast majority of drug prices are set in contracts and cannot respond to short-term shortages.  In addition, pharmacy benefit managers and other drug purchasers are buying in such large quantities that they put pressure on prices.  Finally, when shortages occur, manufacturers may not have necessary capital to expand production.

While it might seem a simple solution to allow importation of drugs that are in shortage, the FDA needs to be sure that imported drugs are safe and effective and manufactured in a facility that meets FDA standards.  Koh reported that the FDA has done this for a number of critical drugs in shortage including Xeloda, leucovorin and levoleucovorin.

Although FDA currently has no authority to require manufacturers to notify them if they anticipate problems in manufacturing a drug or stopping making it, voluntary reporting enabled the FDA, in collaboration with manufacturers, to avert 38 shortages in 2010 and 99 shortages this year.  Strategies available to FDA include:

• Approving importation of drugs from FDA-approved foreign sources as they did with TEVA for leucovorin.
• Speeding the process of approving another manufacturer for the drug from an average of two years or more to three or four months.
• Expediting the review and reopening of a manufacturing plant or production line closed because it didn’t meet FDA Good Manufacturing Practices inspection.

All of these require that FDA get as early notification of potential disruptions as possible.  To that end, Rep. Diana L. DeGette (D-Colo.) reminded the subcommittee that the Preserving Access to Life-Saving Medications Act (H.R. 2245) would require manufacturers to notify the FDA if they are planning to discontinue a drug at least six months in advance.  For other potential disruptions in manufacturing, the FDA must be notified as soon as the problem is known.  There are penalties for not complying.

In addition, the legislation sponsored in the House by DeGette and Thomas J. Rooney (R-Fla.) would require the FDA to publish information relating to manufacturing problems and drugs in actual shortage on its website.  A companion bill in the Senate (S. 296) has been introduced by Senator Amy Amy Klobuchar (D-MN) and Robert Casey (D-PA).

The gray market that offers drugs in shortage to desperate pharmacists and health care facilities was condemned by several witnesses and subcommittee members.  With markups that average 650 percent and go as high as 4500 percent, gray marketeers usually can’t tell pharmacist buyers where the drug came from, whether it has been safely stored, or whether it is counterfeit.

Among solutions to the crisis offered during the hearing were:

• An early warning system for potential shortages with teeth — such as that offered by the DeGette-Rooney legislation.
• Generic drug manufacturer user fees to strengthen FDA resources to manage drug supply.
• An increase in FDA resources directed at drug supply and drug shortages.
• Incentives for manufacturers to enter the market for generic sterile injectable drugs or to update manufacturing facilities.
• Improved funding for the FDA and its resources.
• Better communication between FDA field inspectors and drug shortage programs so that potential manufacturing shut-downs due to lack of Good Manufacturing Practices can be known early.
• Most of all, good collaboration and communication among manufacturers, the FDA, pharmaceutical distributors, pharmacists and healthcare facilities that buy drugs in shortage, and the doctors and nurses who prescribe and administer them.

Rep. Frank Pallone, Jr. (D-NJ) asked that a statement from Fight Colorectal Cancer be entered in the record.

Want to Help

As Rep. DeGette said, the Preserving Access to Life-Saving Drugs isn’t the whole answer to the drug shortage, but it is a necessary first step.

You can help take that step by asking your Senators and Representatives to support H.R. 2245 and S. 296.

In November, Fight Colorectal Cancer is sponsoring a webinar to help you learn what to do when your doctor is out of a drug that you need.

• What to Do When Your Doc is Out of 5-FU (or Leucovorin…or Irinotecan)
• November 16, 2011
• 8:00 to 9:30 p.m. EST

Sign up here.

This morning the FDA added fluorouracil to its drug shortage list. The American Society of Healthcare Pharmacists (ASHP) has also reported a shortage of fluorouracil (5-FU), a common backbone drug for colorectal cancer chemotherapy.

Two manufacturers have some doses of the drug on intermittent back order and are shipping it as it becomes available.  A third has all dose vials on back order and estimates shipping sometime in the fourth quarter of 2011.

According to the FDA and ASHP:

• APP Pharmaceuticals is shipping fluorouracil intermittently as it becomes available.  They say this is due to increased demand.
• Teva has all fluorouracil injection presentations on back order due to manufacturing delays.  They estimate releasing it in the fourth quarter of 2011.
• Mylan Institutional has 50 ml vials on intermittent back order and is shipping them as they become available.  It is only available for drop shipment orders through wholesalers at this time.  They attribute the shortage to increased demand.

ASHP management suggestions include:

• Consider evaluating the health-care system’s total supply of fluorouracil before beginning patients on combination chemotherapy regimens containing fluorouracil. If adequate supplies are not available, select an alternative regimen.
• Consult a Hematology/Oncology specialist for patient- and neoplasm-specific recommendations.
• Refer to the ASHP Guidelines on Managing Drug Product Shortages for more guidance on developing a multidisciplinary plan when the supply must be allocated.

The ASHP Guidelines for Managing Drug Product Shortages in Hospitals and Health Systems has information about managing drug shortages but also includes a good overview about how shortages arise.

It is possible to use Xeloda® (capecitabine) in place of some 5-FU and leucovorin regimens, but there are important safety concerns to think about.  Some research has found that an immediate switch from 5-FU to Xeloda may mean severe side effects. A waiting period to allow folate build-up in cells may be necessary.  Be sure your doctor is aware of this possibility.

More Information

American Society of Healthcare Pharmacists Drug Shortages: Fluorouracil

ASHP Guidelines for Managing Drug Shortages in Hospitals and Health Systems

The FDA issued a shortage update for leucovorin on July 21, 2011.

While leucovorin remains in shortage from all three US manufacturers, the FDA is temporarily allowing Teva Pharmaceuticals to import calcium folinate solution for injection from Europe. The imported solution is the same strength as  powdered leucovorin calcium for injection once water is added to the US product.

In a Dear Healthcare Professional letter, Teva provides a chart comparing the two products and tells doctors and pharmacists that currently Teva is the only organization with regulatory discretion to import and distribute calcium folinate solution.

Calcium folinate for injection is being imported through the Teva affliate in the United Kingdom.  It is manufactured in Hungary at a Teva facility that meets European Good Manufacturing Practice regulations.

Calcium folinate differs from leucovorin calcium in that:

• It comes as a solution ready for injection while leucovorin is a powder that needs to be reconstituted with water.
• It needs to be refrigerated. Leucovorin powder can be stored at room temperature.
• US bar coding systems may not read Teva UK information correctly so extra care needs to be taken in dispensing it.

Updated information about the leucovorin shortage on July 22, 2011 from the American Society of Healthcare Pharmacists.

An alternative to leucovorin, Fusilev® (levoleucovorin) has been approved by the FDA for treatment of advanced colorectal cancer in combination with 5-FU.

Yesterday’s recommendation by the FDA’s Oncology Drug Advisory Committee (ODAC) that approval of Avastin for breast cancer be withdrawn will not affect colorectal cancer treatment.

Avastin® (bevacizumab) remains on the market in the US and is FDA-approved  for advanced colon and rectal cancer in combination with chemotherapy, both as first-line and second-line therapy.

The public hearing held on June 28 and 29 reviewed the process began  in December, 2010 to withdraw the FDA provisional approval of Avastin for metastatic, HER-2 negative breast cancer.  It did not consider or change other label indications for colorectal, kidney, or small cell lung cancers or glioblastoma.

A final decision on breast cancer will be made by the FDA Commissioner Margaret Hamburg, MD.  Until then the indication for breast cancer will remain on the FDA-approved label.

What’s Behind the Hearing?

In 2008, using a procedure called accelerated approval, the FDA gave provisional approval for Avastin to be used to treat metastatic breast cancer based on a randomized clinical trial that showed it took about 5.5 months longer for tumors to get worse (progression-free survival) for women with who received Avastin in addition to chemotherapy than for those who got chemo alone.

However, the provisional approval required that Genentech, the manufacturer of Avastin, conduct further clinical studies to show that the medicine did more — that it actually improved overall survival time.

However, none of the new studies found that survival time increased with Avastin, and they found shorter progression-free survival times than the first trial.  In addition, there were more serious, sometimes life-threatening, side effects associated with using the drug.

In July 2010, ODAC voted to remove the metastatic breast cancer indication from the label.

In December of 2010, FDA announced that they were beginning the process of removing the indication.  Genentech objected to the decision and asked for an new ODAC hearing, which was held this week.

In an unusual step, FDA allowed testimony from advocates and breast cancer survivors at the beginning of the hearing.  In a highly emotionally-charged atmosphere, some so-called “super-responders” told personal stories of successful treatment with Avastin and chemotherapy.

However, at the end of the day, ODAC voted 6-0 that the required further studies had failed to show a clinical benefit when Avastin was added to chemotherapy for metastatic breast cancer.  They further voted 6-0 that the drug was not shown to be safe in those trials, with a 13% higher rate of toxic side effects.

Further written comments from Genentech, the Center for Drug Evaluation and Research, and the public will be accepted until July 28, 2011.  After that the question will closed until Dr. Hamburg makes her decision.

Should the label indication be withdrawn, Avastin can still be prescribed off-label for metastatic breast cancer, but insurance reimbursements for the expensive drug may be in jeopardy.

At the end of yesterday’s hearing the FDA updated its Avastin information, writing:

Following the closing of the docket, the Center for Drug Evaluation and Research will await Commissioner Hamburg’s final decision on Avastin’s use for metastatic breast cancer. The Commissioner’s decision related to breast cancer will not affect Avastin’s approved indications for use in colon, lung, kidney, and brain cancers. That is, regardless of the final decision on metastatic breast cancer approval, Avastin will remain on the market.

What’s the Situation for Avastin and Colorectal Cancer

The ODAC decision does not affect colorectal cancer.  It remains an FDA labeled indication for both first and second line treatment of metastatic (stage IV and recurrent) colorectal cancer.

Avastin was first approved in 2004 for first-line treatment of colorectal cancer when randomized studies showed that it added a median of about five months of life to irinotecan-based chemotherapy alone.

Two years later, second-line therapy for colorectal was added as an indication on the Avastin label, again based on increased survival time when added to FOLFOX chemotherapy.

What About Side Effects?

The clinical trials leading to colorectal cancer approvals found serious, but uncommon side effects, including formation of holes in the colon (gastrointestinal perforation) generally requiring surgery and sometimes leading to abdominal infections, impaired wound healing, and bleeding from the lungs or internally. More common, but less serious, side effects included high blood pressure, fatigue, blood clots, diarrhea, decreased white counts that lowered immunity to infection, mouth sores, and loss of appetite.

Genentech and the FDA also issued two safety warnings in 2004 and 2006:

• A doubling of the risk of serious arterial thromboembolic events, including strokes, heart attack, transient ischemic attacks (TIAs), and angina.
• A rare risk of reversible posterior leukoencephalopathy syndrome (RPLS), a rare brain-capillary leak syndrome.

In 2007, the FDA updated the Avastin label warning of fistula formations,in some cases with fatal outcome. Fistulas involved holes between lungs and esophagus, areas in the lungs, the vagina, bladder, and biliary tract. Events were reported throughout treatment with bevacizumab, with most events occurring within the first six months.

These adverse events and warnings are included on the Avastin label.

By a vote of 217-203 the House approved the fiscal year 2012 agriculture appropriations bill (H.R. 2112). The bill includes funding for the FDA.

Total funding for the FDA, including user fees, is $3.7 billion. This is about 0.09% above last year’s funding level which reflects an increase in mandatory programs over $3 billion. This means that the overall total for the fiscal year 2012 agriculture bill is higher than last year’s bill even though the bill cuts millions from the FDA’s budget.

The bill cuts discretionary funding for the FDA by $284 million. This reduction in discretionary funding for the FDA is an 11.5% cut from last year’s funding level. The reduction includes an $87 million cut from the FDA’s food safety budget.

The $284 million in cuts to the FDA’s budget:
• May delay or prevent development and implementation of a regulatory pathway for bio-similars;
• Significantly reduce efforts to stop importation of illegal products;
• Slow efforts to approve generic drugs;
• Undercut our nation’s investment in development of medical countermeasures in the case of pandemic disease or bio-terrorism.

In addition to the $284 million cut in FDA funding, the House also produced a committee report on the bill. Here are a few highlights from the report:
• In order to focus resources, FDA is strongly encouraged to set up a pilot project to expedite imports for highly compliant importers
• In order to achieve independent post-market surveillance, FDA is directed to submit plans to Congress for an independent office to carry out this work.

We have hopes for a higher allocation in the Senate, and will keep you updated as the Senate Appropriations Committee moves forward with their bill.