This week, for instance, Novartis started shipping its flu vaccine, Fluvirin, across the US, while MedImmune, a unit of AstraZeneca, has been talking about shipments of its three-strain influenza vaccine, FluMist. It’s not unusual for vaccine manufacturers to begin making preparations at this time of year, but one particularly interesting piece of influenza news in the headlines this week concerns a novel breath test that shows promise for measuring an individual’s immune response to the H1N1 virus.

The test, developed by researchers from the Cleveland Clinic and Syft Technologies, measures biomolecules (exhaled nitric oxide) that accumulate in response to H1N1. By identifying people who have already been infected with the virus (and who are thus extremely unlikely to contract the same strain again), the test could reduce unnecessary vaccinations. There’s nothing wrong with being vaccinated against a flu you have already caught, but it does put a bit of a drain on vaccine stocks, which can be scarce depending on public demand.

According to a press statement describing the breath test research, in 2009, more than half of the people in Glasgow (Scotland, UK) who were vaccinated against H1N1 had already been infected with the virus. It’s believed that similar patterns would have been seen throughout the UK. Given the fact that the 2009 swine flu pandemic is still fresh in everyone’s minds, it’s likely that demand for flu vaccines will be high over the next few years so it’s important to make sure that stocks do not go to waste.

There’s still a way to go though before the test can be used commercially. According to the researchers, further work is needed to identify other compounds that are associated with an immune response. It will also be important to identify the exact mechanism that underlies the increase in exhaled nitric oxide triggered by the virus.

It’s definitely an interesting piece of research, but the problem with any influenza R&D is that it can become out of date quickly. By the time an H1N1 breath test is available, it could be that a new strain is filling the headlines and that nobody really remembers H1N1. On a more positive note, though, the research demonstrates the potential benefits that breath analysis can offer to medical diagnostics. And if/when a test does become available for H1N1, perhaps there will be potential to create tests for other strains.

If you’re interested in this research, the full scientific article is available for free (for a limited time) in IOP Publishing’s Journal of Breath Research.

Cases of narcolepsy with a potential connection to the vaccine first began hitting headlines in August 2010, prompting the European Medicines Agency (EMA) to launch a safety review. Six months on, however, it’s not entirely clear what’s going on. Is there a connection? Possibly, but only in certain countries and a certain age group! Although cases of narcolepsy have been reported in at least 12 countries, the majority of these come from Sweden, Finland and Iceland in children and adolescents aged 4–19 years.

“Even at this stage, it does not appear that narcolepsy following vaccination against pandemic influenza is a general worldwide phenomenon and this complicates interpretation of the findings in Finland,” explained a statement from the WHO.

The issue is also further confounded by the fact that an increased risk of narcolepsy has never been observed in association with the use of any vaccine — whether against influenza or other diseases — before.

Finland’s National Institute for Health and Welfare has been heavily involved in investigating the issue and established a National Narcolepsy Task Force last year. According to a report from the task force, 60 children and adolescents aged 4–19 years fell ill with narcolepsy in 2009–2010. Of these cases, almost 90% had received Pandemrix.

“Based on the preliminary analysis, the risk of falling ill with narcolepsy among those vaccinated in the 4–19 years age group was 9-fold in comparison to those unvaccinated in the same age group,” said a press statement from the National Institute for Health and Welfare.

Who’s to blame?

But given that no other vaccine has ever caused narcolepsy before, is Pandemrix really to blame?

A number of countries used similar pandemic vaccines in 2009, but the sharp increase in narcolepsy cases only seems to have occurred in Sweden, Finland and Iceland. Iceland has also reported greater than expected numbers of narcolepsy cases in unvaccinated children and teenagers in the country. GSK believes it’s too early to draw conclusions until the European investigation has been completed, but the company says it is working closely with the EMA to understand the situation.

Narcolepsy has also been shown to have a strong genetic linkage to a specific genotype, which all of the people diagnosed with narcolepsy during 2009–2010 in Finland possessed. The WHO explained that the National Institute “considers it most likely that the Pandemrix vaccine increased the risk of narcolepsy in a joint effect in those genetically exposed with some other, still unknown, genetic and/or environmental factor”.

For now, there’s no clear picture of exactly what is happening. According to GSK, more than 31 million doses of the vaccine have been administered worldwide in 47 countries, with only 162 cases of narcolepsy reported to GSK as of 31 January 2011.

The European Centre for Disease Prevention and Control, in collaboration with a number of EU member states, including Finland, is currently conducting epidemiological studies of narcolepsy and pandemic influenza vaccines. These studies will evaluate the contribution of pandemic vaccines and other risk factors to narcolepsy, and confirm whether an increase in narcolepsy has been seen in other countries. The outcomes of the study will be announced this summer.

As for children under 10, NIAID said they “had a less robust early response to the vaccine” and that this follows the pattern of seasonal flu vaccine responses in younger children. For this reason, it is likely that they will need two doses of the H1N1 flu vaccine.

“These results are not unexpected and are both similar to what is seen with seasonal influenza vaccines and consistent with what we and our colleagues at the Food and Drug Administration anticipated,” NIAID Director Anthony S. Fauci said in the announcement.

Also announced this week, Sanofi Pasteur received an additional order for the H1N1 flu vaccine from the US Department of Health and Human Services. Sanofi will produce an additional 27.3 million doses for the government’s pandemic response plan, bringing the total to 75.3 million doses. Sanofi’s vaccine is used in the children’s vaccine trial, and is one of the four approved by FDA on Sept 15.

But clinical trials of the vaccine are still underway on pregnant women and children, two groups that the Centers for Disease Control and Prevention (CDC) says are especially vulnerable to the H1N1 flu. CDC has identified five priority groups to receive the vaccine once it becomes available: pregnant women, people who live with or care for infants, healthcare and emergency medical services personnel, people between 6 months and 24 years old, and adults with chronic conditions ages 25–64. CDC estimates these populations total approximately 159 million people in the United States.

CDC’s Q&A document titled “2009 H1N1 Influenza Vaccine and Pregnant Women” says certain populations, including pregnant women, may need two doses. That will be confirmed when the data from the clinical trials are in. The National Institutes of Allergies and Infectious Diseases (NIAID) began the initial clinical study in pregnant women on Sept. 9, and it involves up to 120 women, ages 18–39, in their second or third trimester of pregnancy. Participants received an initial injection and will get a second shot 21 days later. Samples of the women’s blood and of the cord blood will measure the immune response and the presence of maternal antibodies crossing the placenta to the infants. NIAID plans to conduct studies at six medical centers nationwide.

FDA’s statement on Tuesday said that ongoing clinical studies of the vaccine in children will point to the appropriate dosage. The agency expects to know for sure “in the near future.”

Safety of the vaccine is a concern for pregnant women and parents. After all the efforts and recommendations of government agencies and vaccine manufacturers around the world, will pregnant women and parents want it? CDC says, “We do not expect that there will be a shortage of 2009 H1N1 vaccine, but availability and demand can be unpredictable.” What if the demand is significantly below what CDC is expecting?

A report on NPR Health Blog says that only about 15% of pregnant women get the seasonal flu shot, despite recommendations by CDC. “The swine flu vaccines are not specifically approved for pregnant women. But neither are ordinary seasonal flu vaccines. The reason, says FDA, is that the agency doesn’t specifically approve most adult drugs for categories of adults, such as pregnant adults,” according to the article, which also suggests that obstetricians do not urge their pregnant patients to get seasonal flu vaccines. Perhaps that is due to this text found on the vaccine labels, explains the article:

“If you look at the fine print on seasonal flu vaccine labels, you’ll see language like this: ‘It is not known whether (this vaccine) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. (This vaccine) should be given to a pregnant woman only if clearly needed.’”

Without strong recommendations from their OBs, pregnant women may not want to line up to get the H1N1 shot when it becomes available.

Uncertainty about the safety of the H1N1 vaccine is evident on community message boards and on websites, such as the pregnancy-focused babycenter.com. In the “Swine Flu Discussion Group,” some moms-to-be are skeptical of the new vaccine, calling it “rushed” or “not tested enough” and generally calling into question the vaccine’s safety, given the speed at which it was produced, and effectiveness against the new form of the flu.

This week, a Los Angeles Times article reported that some parents refuse to vaccinate their children against H1N1, preferring them to catch the virus and develop a natural immunity. Physicians say that young parents could refuse the vaccine for their children for a number of reasons, including fears of a link between vaccines and autism, the fact that many of the parents grew up not knowing about once-common childhood diseases, wariness of a vaccine that is still being tested, and a “distrust of drug manufacturers, media outlets and the federal government,” according to the article.

People remain unsure about the H1N1 vaccine despite FDA’s and CDC’s reassurances that it is made by trustworthy manufacturers using established procedures. In this week’s FDA release, Jesse Goodman, FDA acting chief scientist, says, “The H1N1 vaccines approved today undergo the same rigorous FDA manufacturing oversight, product quality testing, and lot release procedures that apply to seasonal influenza vaccines.” The statement also pointed out that the four vaccine manufacturers “have a long record of producing safe seasonal influenza vaccines.”

Despite public uncertainty, the H1N1 shot is recommended as the best way to prevent catching the virus and avoid complications from it—in addition, of course, to proper hand washing and avoiding sick people. As CDC says in its Q&A document on the vaccine’s safety, “CDC and FDA believe that the benefits of vaccination with the 2009 H1N1 influenza vaccine will far outweigh the risks.”

Kalorama Information’s recent market-research report titled “Drug Delivery Markets” predicts a heightened interest in needle-free and implantable delivery methods for vaccines. The report describes the potential growth in delivery devices, particularly autoinjectors and pen injectors such as the EpiPen. Formulation techniques such as PEGylation, microspheres, and nanoparticles make up another portion of the report.

The document also includes inhaled insulin, that tantalizing prospect for diabetics that has not yet found commercial success. For example, Kalorama mentions the ProMaxx pulmonary-insulin product that Baxter Biopharma Solutions (Round Lake, IL) is developing. The report also assesses the prospects of drug-delivery companies such as Alkermes (Cambridge, MA) and Nektar (San Carlos, CA) that have tried to develop inhaled insulin.

This report is another reminder that vaccines and other biologicals seem to be where the excitement is in the drug industry today. Even if the industry’s pipelines are not impressive, it looks like innovations will still emerge in the form of drug-delivery methods. Who knows, maybe the demand for biopharmaceuticals will inspire the development of unconventional ways to administer vaccines. MedImmune’s (Gaithersburg, MD) inhaled swine-flu vaccine could point the way for other therapies.

And today’s research will almost surely affect the way we deliver small-molecule drugs, too. Maybe the dominance of oral solid-dosage forms will end in the not-too-distant future. The economic pressures that are leading the industry to focus on drug-delivery methods make this a distinct possibility.

In March, the US Attorney’s Office for the Southern District of Texas announced that Richard Fletcher was convicted of conspiring to distribute counterfeit pharmaceuticals and trafficking in pharmaceuticals bearing false labeling and counterfeit trademarks. An investigation involving Immigration and Customs Enforcement and the US Food and Drug Administration’s Office of Criminal Investigations showed that Fletcher sold counterfeit erectile-dysfunction drugs Viagra, Cialis (Eli Lilly, Indianapolis) and Levitra (Bayer, Leverkusen, Germany) via a website that he owned, and that he had obtained the counterfeit drugs online from a source in China. Fletcher also “discussed techniques to evade detection and seizure by law enforcement officials with individuals residing in China,” according to a US Attorney’s Office press release.

Fletcher pleaded guilty to both federal offenses and faces up to 10 years in federal prison, without parole, a $250,000 fine, and a maximum of three years of supervised release after the prison term. Fletcher is scheduled to be sentenced on Sept. 22, 2009.

It’s too early for counterfeit swine flu vaccines to appear online, but this spring the Internet was immediately populated with websites offering unapproved products to treat the H1N1 influenza virus. On May 1, FDA warned consumers about illegal products marketed through the Internet related to the 2009 H1N1 flu virus. The agency has issued more than 50 warning letters to offending websites. The warning letters show that, hoping to cash in on a worldwide crisis, companies offered various unapproved products, from swine flu kits to nasal sanitizers to antiviral herbal remedies, with claims such as, “One pack is enough for a family of four to prevent winter colds and influenza, including swine flu, if you have been exposed,” and an air purifier that promises to be “tested and proven effective at controlling and killing bird avian flu, SARS, anthrax spores, and now Swine Flu!” Since early May, FDA says more than 66% of these websites have removed the offending claims and/or products.

Ordering pharmaceutical products online can be risky if the proper precautions are not taken by the consumer. The World Health Organization estimates that half of all pharmaceutical sales from Internet websites that conceal their physical address are counterfeit or adulterated.

Perhaps what is needed is more education and awareness for consumers. FDA’s web page on counterfeit drugs offers helpful information about how to avoid counterfeits by using only pharmacies licensed in the United States. An article explains how to shop safely online by looking for the VIPPS Seal, or the seal of the Verified Internet Pharmacy Practice Sites Accreditation Program. Resources for verifying the good standing of pharmacies and the VIPPS Seal certification are provided. FDA’s Counterfeit Medicines page also contains a link to report a website that may be selling counterfeits.

If consumers seek information on how to protect themselves from counterfeit drugs, FDA provides that information clearly and effectively—but do people know that they can and should be looking for it? For example, do most people know to check for the VIPPS Seal before purchasing from an online pharmacy? Maybe a greater effort to let people know that they can get involved in fighting counterfeiting would be a step toward greater public safety.

For more on the pharmaceutical industry’s anticounterfeiting efforts and supply-chain security, see Pharmaceutical Technology’s recent special report.

As of today, nearly 30,000 confirmed cases have been reported in 74 countries. And as Chan observes, “This is only part of the picture. With few exceptions, countries with large numbers of cases are those with good surveillance and testing procedures in place.”

“Further spread is inevitable,” said Chan in a statment to the global press.

Currently, the infection has been of moderate severity and, says Chang, thanks to pandemic preparedness programs, no other pandemic has even been detected so early or watched so closely.

As an industry, pharmaceutical companies worldwide continue to work with local and international healthcare organizations and regulatory agencies to develop antivirals and vaccines.

See related blog posts and news coverage by Pharmaceutical Technology.

In accordance to an existing contract, HHS has placed an initial order, valued at $190 million, with Sanofi Pasteur for a vaccine. The order provides for the production of the bulk vaccine. However, the company is still awaiting the seed virus from the US Centers for Disease Control. Once the seed virus is obtained, the company says it will have a better timeline of when the vaccine might be available. Moreover, dosage requirements have not yet been determined and the final formulation, filling, and distribution of the vaccine have not yet been established. Sanofi Pasteur also says it “is prepared to commence commercial scale production in June following certification of the working seed by the US Food and Drug Administration.”

Meanwhile, HHS has also placed initial orders for influenza A (H1N1) antigen from GSK as well as the company’s proprietary AS03 adjuvant system, which the company already used in phase II trials of an adjuvanted influenza A H5N1 (avian flu) vaccine. According to a May 15 release, GSK says it is also waiting on a seed virus from the World Health Organization. The company claims it has also received “several orders from several governments” for an influenza A (H1N1) adjuvanted vaccine. The governments of France, Finland, Belgium, and the United Kingdom were listed in this release.

Perhaps future vaccine production will take a completely different approach. In a previous post, I questioned what would happen if the H1N1 virus became resistant to current antiviral drugs. Evidently, a team of researchers is already on their way to solving that potential problem. At Rensselaer Polytechnic Institute in Troy, NY, work is underway to test a new approach for combating the influenza A virus, including its possible mutations. In an announcement made May 19, scientists said they are seeing “promising preliminary results” of a chemical approach to targeting both the hemagglutinin (H) and neraminidase (N) outer protein components of the influenza A virus. Current influenza drugs target only the N portion, which disrupts the ability of the virus to leave an infected cell and infect other healthy cells. The new approach, based on “click chemistry,” targets the H protein, which prohibits entry into the healthy cell. The research team says they can manipulate the chemistry to target one or both components depending on the mutation (e.g., H1N1 associated with swine flu or H5N1 associated with avian flu).

In response to the swine-flu outbreak, the European Medicines Agency (EMEA) last week authorized the use of Tamiflu (oseltamivir) capsules up to two years after the drug’s prescribed expiration dates. EMEA’s Committee for Medicinal Products for Human Use (CHMP) specifically extended the shelf-life of Tamiflu 75 mg, 45 mg, and 30 mg hard capsules from 5 to 7 years.

Here’s the background: According to the CHMP report, there are currently two classes of antiviral drugs available to treat influenza: adamantane inhibitors (amantadine and rimantadine) and neuraminidase inhibitors (oseltamivir and zanamivir). Studies of the swine-flu virus detected in humans in Mexico and the US were found to be resistant to amantadine and rimantadine, according to the report, so those antivirals were not reviewed. Instead, EMEA focused on oseltamivir, marketed as Tamiflu by Roche, and zanamivir, marketed as Relenza by GlaxoSmithKline. EMEA worked with the drug manufacturers and other experts to review drug safety reports before making their decision. The goal, according to the report, was to avoid a shortage of potentially effective influenza treatments by making sure expired or soon-to-expire capsules were not discarded. Tamiflu’s potential shortage was most imminent, according to the report.

EMEA’s shelf-life extension of Tamiflu does not extend to the pediatric version of the drug. CHMP, therefore, still plans to investigate the drug’s usage for children under age 1 and for pregnant and breastfeeding women, but in case of emergency, has given guidelines for using Tamiflu to treat these patients. Relenza, which is indicated for treatment of influenza in patients over age 5, according to the document, is also still being researched although it was noted as acceptable for use in pregnant women in the case of a full-blown pandemic.

CHMP also noted that storage conditions for Tamiflu are important for maintaining stability. The capsule boxes must remain stored below 25 °C (77 °F).

I’m glad EMEA made this move—to quickly research and make a decision that could potentially save lives. But it also makes me wonder how many other products’ expiration dates could be extended. From time to time, I’ve been known to take an Advil or Tylenol from my medicine cabinet even if it had expired a few weeks before. I figure the drug can’t go that bad just a few weeks after the expiration date, besides, how many people forget to double-check expiration dates? But looking ahead, maybe some money could be saved here. If drugs last longer than we think they do, we wouldn’t have to throw out unused—and potentially still safe and effective—medication. This possibility may be worth looking into even when a pandemic isn’t present.

See FDA’s viewpoint on these antivirals.

A recent report by the International Federation of Pharmaceutical Manufacturers & Associations (IFPMA) said that the pharmaceutical industry provided health interventions (i.e., medicines, vaccines, training, and education) to nearly 1.4 billion people in developing nations at a value of $6.7 billion between 2000–2006. The same report cites results of a survey by the Committee Encouraging Corporate Philanthropy, a corporate philanthropy forum of global company CEOs, which surveyed 136 major corporations’ giving in 2006. Overall, it found that companies gave an average of 0.88% of their pretax profits, but within the health sector (in which 10 out of 16 companies were pharmaceutical companies), the average was higher at 3.70%.

The IFPMA report provides an overview of long-term health development programs implemented by the research-based pharmaceutical industry and partners to help achieve the health-related Millennium Development Goals (MDGs) of the United Nations. The MDGs were adopted by 189 United Nations’ member states in 2000 as part of a global health initiative with one goal being to improve ways to combat HIV/AIDS, malaria, and other diseases that particularly afflict the developing world.

The IFPMA report provides examples of how companies are improving access to basic medicines and critical treatments such as HIV/AIDS therapies through reduced pricing and improved distribution as well as through original research to develop drugs to treat neglected diseases. These efforts are being encouraged through international organizations such as the United Nations, the World Health Organization, developed countries, and nongovernmental organizations. Corporate philanthropy is an important, although certainly not a complete solution, to combat the medical problems of developing nations, but is an area in which all efforts, including new models, should be recognized and further encouraged.

One such effort is the work of The Institute for OneWorld Health, which characterizes itself as the first nonprofit pharmaceutical company in the United States. The company has a specific corporate mission to address unmet medical needs in developing countries through pharmaceutical product development by providing drug lead identification and optimization, conducting clinical trials, and securing regulatory approvals of new medicines. The company was founded in 2000 by Victoria Hale, who held positions with Genentech and the US Food and Drug Administration, and who now serves as the company’s chair emeritus.

The group’s projects include the development of a semisynthetic route to artemisinin; artemisinin derivatives are used in combination therapies to treat malaria. Artemisinin is derived from the wormwood plant in Asia and Africa, and the goal of the project is to create a complementary source of nonseasonal, high-quality, and affordable artemisinin to supplement the current botanical supply and meet future demand for artemisinin-based combination therapies. The project is funded and supported by the Bill & Melinda Gates Foundation, the California Institute of Quanitative Biomedical Research at the University of California at Berkeley, Amyris Biotechnologies, and sanofi-aventis.

The artemisinin project shows the innovation in the business models and partnerships that can be used to address the medical needs of the developing world. It is hoped that the pharmaceutical industry and others will continue and deepen these efforts.