After reviewing its documentation, the company concluded that routine preventive maintenance and requalification of manufacturing equipment at the site was overdue. Ben Venue suspended manufacturing so that it could assess the entire site and take appropriate corrective actions to ensure the safety of its products. The suspension will affect Johnson & Johnson, which markets Doxil, as well as Pfizer, Hospira, and Teva.

Last month, President Obama ordered FDA to take various steps intended to prevent and reduce drug shortages. The agency will require advance notice from manufacturers likely to face manufacturing disruptions, and it will expedite reviews of new drug suppliers, production sites, and manufacturing changes.

These steps, while helpful, do not address an important factor that contributes to drug shortages: manufacturing deficiencies. Even before Ben Venue conducted its own review, FDA found 48 quality concerns during an inspection of the Bedford site in May 2011. FDA likely needs a larger pool of inspectors to oversee drug manufacturing sites more thoroughly. But the government’s current desire for austerity will probably preclude the budget increase that would make hiring possible.

Maybe FDA should prioritize manufacturing sites for inspection if they are among a few that produce a medically necessary drug such as Doxil. Greater attention to crucial sites could identify problems earlier and, ideally, resolve them without disrupting drug supply.

The National Institutes of Health recently administered cancer vaccine PANVAC to 26 women with breast or ovarian cancer. PANVAC, a recombinant poxviral vaccine, produces two proteins associated with tumor cells to stimulate the body’s immune system to attack the cancer. During the trial, the median time it took for the breast-cancer patients’ condition to progress was 2.5 months, and the patients’ median survival time was 13.7 months. One breast cancer patient was still alive 37 months later. Median survival for the 14 ovarian-cancer patients was 15 months, and one woman went 38 months before her disease progressed. Although the trial was small and did not include a control group, these results seem encouraging.

Researchers from Oxford University also have attempted to fight cancer with the immune system. A team led by Paul Fairchild, codirector of the Oxford Stem Cell Institute, used stem-cell technology to create new dendritic cells from a patient’s skin. The dendritic cells, which organize part of the body’s immune response, carried the marker Melan A so that they would trigger an attack on melanomas. In the study, the team’s dendritic cells activated immune cells that produce antibodies and those that kill other cells. Previous studies using other dendritic cells had stimulated only part of the immune system.

Both of these techniques are still in their early phases. It will be some time before the studies lead to therapies from which patients can benefit, but they add to our knowledge of cancer and underscore the importance of oncology research. I take encouragement from these early steps, which I hope will inspire other drugmakers to take up the challenge of battling cancer.

This week, it wasn’t a vegetable that commanded the media’s attention (although this morning I did come across a piece touting the benefits of spicy broccoli for fighting cancer); instead, the flower, the British Autumn crocus, stole the spotlight following the release of a press statement from the UK’s University of Bradford. According to the statement, researchers have created a drug that has the potential to find and destroy solid tumours, regardless of cancer type.

The drug’s key active agent is based on colchicine, a natural compound that was derived from the crocus. Most media headlines have sensationalised the research (examples include: Tumors effectively cured with crocus drug,  Crocus drug that can kill tumours in one treatment with minimal side effects and Flower-powered ‘smart bomb’ to beat cancer, scientists say), but when you look beyond the hype, there’s some intriguing science.

Colchicine is well-known for its anti-cancer properties, but is highly toxic against normal tissues in the body. The researchers, however, have designed a delivery system that prevents colchicine from being active around the rest of the body where it could damage normal cells. The release of colchicine is triggered by an enzyme from a family of proteases called Matrix Metalloproteinases (MMPs), which is only usually present in high amounts in tumours.

“One role of this particular MMP in cancers is to dig a path for the tumour to grow bigger and develop new blood vessels that will help nourish the tumour,” Professor Laurence Patterson, Director of Bradford’s Institute for Cancer Therapeutics (ICT), explained in a statement. “Our novel delivery method uses the presence of this active MMP to activate the drug which attacks and breaks down cancer blood vessels, destroying the tumour’s lifeline.”

Five different types of cancer have been tested in the laboratory using mice — breast, colon, lung, sarcoma and prostate. According to the researchers, in one study, half the mice showed complete tumour remission after a single dose. The team is now in discussion with a funder to take the drug through the final stages of preclinical assessment, after which clinical trials are planned to start at St James’s University Hospital in Leeds.

Back to reality

The research (and the accompanying media sensationalism) has caused a massive stir, but the UK’s Cancer Research was charity was quick to point out in a detailed blog that the research is a long way from curing human cancers. There’s also no guarantee that it will ever be possible to translate the findings into humans (see my related blog post A Rat is Not a Human!).

Cancer Research also points out something else; the press release seems to be based on peer-reviewed work that the researchers published in July 2010. “As far as we’re aware, the team haven’t published any new results since their 2010 paper,” said Cancer Research.

It’s not all disappointing news, however. The research is still a step forward in the fight against cancer and Cancer Research admits that the research is intriguing, although it does remain cautious in its outlook.

“The researchers’ results so far are impressive, but they’re just one of several hundreds of similar intricate approaches taken to tackle cancer by researchers around the globe, which are generally referred to as ‘enzyme-prodrug therapy’, and involve activating a harmless form of a drug near or in a tumour… Overall it’s fair to say that this kind of approach is still at a relatively early stage, although the Bradford results are certainly impressive, and their beauty is in their relative simplicity.”

Related blogs and news from PharmTech
Sensationalizm Strikes Again

Research Spend On Cancer Doubles Within A Decade

A Rat is Not a Human

The capsules, which are made of polymeric hydrogels, are hollow except for polymer chains that are linked to the interior of the shell. These chains divide the capsule’s interior into various compartments that could contain several active ingredients. Possible applications include cancer therapy and pain relief.

The researchers formed the capsules in a two-step process. First, they formed chains of a temperature-sensitive polymer without using a cross-linking agent. The absence of this agent causes the chains to dissolve at a certain temperature. Next, the scientists added a cross-linking agent to a second polymer to create a shell around the temperature-sensitive polymer chains. Cooling the microcapsule caused the shell to swell until it reached its stable size, leaving behind temperature-sensitive polymer chains that can act as hydrophobic drug carriers.

The scientists are still trying to determine the best way to load drugs into the capsules and the best way to trigger them to release the drugs. Even though the capsules are still being refined, they have the potential to become a useful drug-delivery tool. Polymeric microspheres, while not new to the drug industry, can be a versatile delivery method. The straightforward process for creating the capsules also could attract drugmakers’ attention. The Georgia Tech team’s work provides cause for optimism at a time when some observers lament the lack of innovation in the drug industry.

The research, including the harmless operation of the magnetic pill system in rats using conventional gelatine capsules, was described earlier this week in the Proceedings of the National Academy of Sciences by researchers from Brown University in the US.

“With this technology you can now tell where the pill is placed, take some blood samples and know exactly if the pill being in this region really enhances the bioavailability of the medicine in the body,” Edith Mathiowitz, Professor of Medical Science in Brown’s Department of Molecular Pharmacology, Physiology and Biotechnology, said in a press statement.

In particular, the researchers envision that the technology could be used as a new drug delivery method for cancer drugs or drugs targeting GI diseases, as there are a number of therapeutics that would benefit from prolonged localization at their site of action or at the site of greatest absorption.

This is not the first time researchers have been attracted to the idea of controlling tablets magnetically, but, according to the press statement, it is the first time that magnetic forces have been controlled sufficiently to make the system safe for use in the body. The system developed by the Brown University researchers senses the position of tablets and holds them there with a minimum of force.

“The most important thing is to be able to monitor the forces that you exert on the pill in order to avoid damage to the surrounding tissue,” said Mathiowitz. “If you apply a little more than necessary force, your pill will be pulled to the external magnet, and this is a problem.”

The research is still in the early preclinical stages, but it’s promising that the researchers have been able to overcome the hurdle of making the system safe for use in the body. According to the statement, even after holding a pill in place for 12 hours in the rats, the system applied a pressure on the intestinal wall that was less than 1/60th of what would be damaging.

The next step will be to use the system to deliver drugs and test their absorption.

“Then it will move to larger animal models and ultimately into the clinic,” Bryan Laulicht, the lead author of the study, explained. “It is my hope that magnetic pill retention will be used to enable oral drug delivery solutions to previously unmet medical needs.”

Nowhere is the importance of producing more efficacious drugs more apparent than in the area of cancer. Almost 40 years ago, 1971, to be exact, then President Richard Nixon directed in both words and action what has become a difficult battle for the pharmaceutical industry to win, “The War on Cancer,” by signing into law the National Cancer Act (P.L 92-218). This law gave the National Cancer Institute increased autonomy and budgetary authority to “more effectively carry out the national effort against cancer.” In a speech before a joint session of Congress last February, President Barack Obama reaffirmed that commitment through a call for “a new effort to conquer a disease that has touched the life of nearly every American by seeking a cure for cancer in our time.” But where do we stand on the pledges made decades ago and again now?

According to a 2009 report by the Pharmaceutical Research and Manufacturers of America (PhRMA), since 1980, life expectancy for cancer patients has increased about three years, and 83% of those gains are attributable to new treatments, including medicines. Another study cited in the PhRMA report found that medicines specifically account for 50% to 60% of increases in survival rates since 1975. But cancer still remains the second leading cause of death in the US, affecting more than 10 million people each year, according to data by the National Cancer Institute cited by the PhRMA report.

The cancer pipeline of US pharmaceutical and biotechnology companies is deep and reached a record level in 2009. There are 861 anticancer drugs and vaccines in human clinical trials or awaiting approval by the US Food and Drug Administration, according to a PhRMA report on cancer drugs. These drugs include 122 drugs to treat lung cancer, the leading cause of cancer death in the US, 107 therapies to treat breast cancer, 103 for prostate cancer, 70 for colorectal cancer, and many more for other forms of cancer. With the time to develop a drug estimated at between 10 and 15 years, that means that our best current hope to make good on the pledge to win the war on cancer in this new decade is already before us.

For sure, this past decade has seen scientific advances through ongoing development and commercialization of more targeted cancer therapies. Monoclonal antibodies, recombinant proteins, select small molecules, prophylactic vaccines, and improved drug delivery methods continue to hold great promise. Ten years from now, I hope that I can dust off the PharmTech archives with an addendum to this blog to chronicle the gains in cancer treatment made in the decade of 2010, which first began in the year 2010. That is one resolution worth making and one in which we can hope to be able to meet.

CIRM was established in early 2005 following the passage of Proposition 71, the California Stem Cell Research and Cures Act, which provided $3 billion in funding for stem-cell research at California universities and research institutions and called for the establishment of a new state agency to make grants and provide loans for stem-cell research, research facilities, and other research opportunities. In the recent funding announcement, CIRM is providing the bulk of the funding. The UK’s Medical Research Council is providing $8 million, and Canada’s Stem Cell Consortium is providing $35 million to fund the international portions of the research collaborations.

To speed the process of establishing clinical trials for the stem-cell-based therapies, the research teams receiving the funding will include basic scientists and clinicians from academia and industry. “Scientists have talked for years about the need to find ways to speed the pace of discovery,” said CRM President Alan Trounson in the CIRM release. “By encouraging applicants to form teams composed of the best researchers from around the world, we think CIRM will set a new standard for how translational research should be funded.”

Ten of the 14 disease-team projects being financed involve the use of “adult” stem cells, many involved in cancer treatments, and four projects will involve the use of human embroynic stem cells. Some project highlights include the use of neural stem cells for developing treatments for brain cancer, the development of three monoclonal antibodies and three small molecules for destroying leukemia stem cells, RNAi-based therapies to produce T-cells resistant to HIV infection, a gene-therapy approach to modify blood-forming stem cells to produce red blood cells, and using cardiac stem cells to repair damaged heart tissue .

The diversity of the disease targets from these research projects shows the promise of regenerative medicine in pharmaceutical research and development, and the recent funding is a good start toward realizing its potential.

The first was the emergence of competition for Merck’s vaccine. The US Food and Drug Administration approved GlaxoSmithKline’s (GSK, London) Cervarix, which clinical trials found to be effective in preventing precancers caused by HPV types 16 and 18, which are the most common. Cervarix had already received approval from international regulators, but it may have difficulty getting traction. Unlike Gardasil, it does not combat HPV types 6 and 11, which cause cancer and genital warts.

We noted in ePT that Natalie Morton, a 14-year-old girl, died after receiving Cervarix in September 2009. GSK expressed its sympathies to the girl’s family and recalled a batch of the vaccine. The cause of Morton’s death is under investigation, but some observers have wondered about Cervarix’s safety.

Perhaps to make assurance of success double sure, Merck had been seeking FDA approval for a new indication for Gardasil. It got this approval on Friday when the agency sanctioned the vaccine for use against genital warts in boys. This apparent coup could expand the market for Gardasil and boost its sales.

Or could it? Gardasil might not be used widely for boys because genital warts caused by HPV usually disappear without treatment. On top of that, researchers from the Harvard School of Public Health and an investigator at the US National Cancer Institute argue that it would not be cost-effective to treat boys as well as girls. In a press release available at the US National Library of Medicine, Jane Kim, the lead researcher of the Harvard team, said that “including boys in an HPV vaccination program generally exceeds what the US typically considers good value for money.”

Even if practicality and economic considerations prevent Merck from capitalizing on its new indication for Gardasil, the vaccine is well established and likely could withstand the challenge from Cervarix. More importantly, the drugs have prompted fruitful discussions about standards for drug efficacy and the public health. These exchanges help us identify and defend our priorities. The drugs have also gotten us thinking about gender equality, which, to my mind, is too often ignored.

Maybe a new development will change the Gardasil story yet again. Stay tuned.

Let’s recap a few major developments to date. At first, ethical concerns hampered progress in stem-cell research when the best way to obtain the cells was to harvest them from discarded embryos. After scientists learned how to create induced pluripotent stem (iPS) cells by deprogramming adult cells, these ethical concerns were rendered moot.

The deprogramming method itself raised problems, however, because it permanently integrated genes with the potential to induce cancer into adult cells to transform them into iPS cells. The resulting stem cells had the potential to cause tumors and were thus not considered safe for use in human patients.

Then, in May 2009, researchers in Wisconsin described a method for creating iPS cells with nonintegrating episomal vectors. In contrast with the previous inducement method, the episomes in this process are lost during cell division, thus leaving the resulting iPS cells free of potentially problematic foreign genes. It therefore became possible to use the same tools in a different way to create iPS cells that were safer than before.

Things changed once again last week when a team at the Harvard Stem Cell Institute found a small molecule that could replace at least one of the cancer-related genes in the inducement process. Like the Wisconsin researchers’ method, the new technique created stem cells that are safer than was previously possible.

These efforts represents various routes toward the goal of creating personalized cells that are safe enough to be the basis of cell-based therapies. The researchers hope that a chemical-based (rather than gene-based) process for creating stem cells would yield therapies that require no immunosuppressive drugs.

These exciting reports have ramifications for research, personalized medicine, and the development of effective new biological drugs. During a challenging time for the drug industry, advances such as these offer hope for the future.

Prostate cancer remains one of the most common cancers and the second-leading cause of cancer death in American men, according to the American Cancer Society. So far, treatments for prostate cancer include drugs that affect the entire body, instead of only cancer cells. Work by a team of researchers at Purdue University offers hope they have found a new method of not only finding and targeting these cancer cells, but also carry therapeutic drugs directly to the site of infection.

The scientists have synthesized what they have termed a homing device: a molecule that finds and penetrates prostate cancer cells. The molecule attaches to a protein that is only present in 90% of all prostate cancers (prostate-specific membrane antigen, or PSMA). If the targeting molecule could be linked to new drugs being designed to destroy the vasculature of solid tumors, says Philip Low, professor of Biochemistry, then the method would kill the cancer cells directly and the vasculature that feeds the tumors.

Scientists have for many years looked to monoclonal antibodies as molecular homing devices. But the Purdue scientists used a rational-design approach. They developed their homing molecule after studying the PSMA structure in computer models.

The team also has developed imaging agents for body scans that can be linked to and be carried by the molecule. Currently, only one imaging agent for prostate cancer cells has been approved by the US Food and Drug Administration. The research team says it hopes to enter its radioimaging application into clinical trials this fall.

 A successful targeted drug delivery system would be a giant step not only in the fight against cancer but also in providing some relief to those who endure the painful side effects associated with existing therapies.