The trial will study a combination of two vaccine candidates, Ad26.ENVA.01 (manufactured by Crucell) and Ad35-ENV (developed by IAVI), in healthy adults who do not have HIV. The trial will focus on the vaccines’ safety and effectiveness as a prime-boost regimen. The goal of a prime-boost combination is that one vaccine is administered to prime the immune system and elicit a certain immune response before a second, or booster, dose is given to enhance the overall immune response.

A previous clinical trial based on a prime-boost combination took place in Thailand and represents the first time an AIDS vaccine showed promise in reducing the risk of infection. Results released in September 2009 showed that the combination of vaccines lowered the risk of acquiring HIV by roughly 30%. Additional data were presented at the AIDS Vaccine 2009 Conference and published in the New England Journal of Medicine. The research team wrote that, “Although the results show only a modest benefit, they offer insight for future research.”

Also announced this week was that the International AIDS Vaccine Initiative (IAVI) appointed Michael Caulfield executive director of the IAVI AIDS Vaccine Design and Development Laboratory (DDL). Caulfield previously held research positions at Merck (Whitehouse Station, NJ) and the Cleveland Clinic. As leader of the DDL, he will be responsible for IAVI’s translational research and vaccine discovery, as well as for expanding its R&D team.

“Mike’s joining at a critical time for the field,” said Wayne Koff, IAVI’s chief scientific officer, in a press release. “We’re in the middle of a renaissance in AIDS vaccine design and development.”

In related news, scientists at the National Institutes of Health (NIH) announced the discovery of two human antibodies that can stop more than 90% of HIV strains from infecting human cells in the laboratory. The team, part of the Vaccine Research Center, a division of the National Institute of Allergy and Infectious Diseases at NIH, also demonstrated how one of the antibodies does this. The scientists said the antibodies could be used to design improved HIV vaccines, or could be further developed to prevent or treat HIV infection, according to the group’s press release. The work was published in Science in two articles, found here and here.

The NIH team’s discovery plus the results of the Thailand vaccine trial are examples of exciting progress in the field of AIDS vaccine research. Many are hopeful that the Crucell clinical trial will add to the upswing of encouraging results.

See previous posts on this topic:

The AIDS Vaccine Challenge

Roche Ends HIV Research Program

Vaccine Makers Prepare for Challenges Old and New

“Without good quality, safe medicines to treat diseases such as HIV/AIDS, malaria and tuberculosis, the impact of other health initiatives may be weakened. The PQM program focuses on this critical aspect of combating these diseases,” Gloria Steele, USAID acting assistant administrator for global health, said in a press release.

“The lives of patients are put in serious jeopardy when they take substandard or counterfeit drugs,” Roger L. Williams, MD, chief executive officer of USP, said in a press release. “Such ‘medicines’ have health as well as economic implications. Moreover, substandard medicines contribute to the development of drug-resistant strains of infectious diseases. Such strains are a leading challenge in the fight against malaria, HIV/AIDS and tuberculosis.”

The PQM program is an expansion of a previous collaborative effort between the two organizations called the Drug Quality and Information (DQI) program. Like the DQI program, PQM will be managed by Patrick Lukulay, PhD, director of drug quality and information at USP, who will work with USAID’s Office of Health, Infectious Diseases, and Nutrition, under the direction of Anthony Boni.

Lukulay told Pharmaceutical Technology that the goals of the PQM program are to build capacity in developing countries to improve quality of pharmaceuticals and quality-control testing, to raise awareness of the importance of drug quality and advise people on how to safely buy medicines, and to conduct research in developing countries on the quality of drugs available on the market.

Lukulay also discussed some future projects of the program, such as the upcoming publication of the results of a study about the quality of malaria drugs in Sub-Saharan Africa and the development of a program that would provide reference material at a reduced cost to African countries to aid in quality testing. PQM is also working on the development and promotion of technology to detect counterfeit drugs using hand-held spectroscopic devices, which provide a nondestructive method of finding fake drugs that is significantly faster than traditional wet-chemistry methods. He also discussed the group’s work in creating adverse-drug-reaction data sheets for use in developing countries and PQM’s efforts to gather pharmacovigilance data.

“We are excited about PQM because it is going to give us the opportunity to expand on the work we started over the past decade,” Lukulay said. Some examples of DQI initiatives include the establishment of large-scale continuous monitoring program for quality in Latin America, Africa, and Asia, which led to the seizure of counterfeit versions of the antimalaria drug Coartem (Novartis) from pharmacies in Ghana in July 2009; increasing the capacity of quality control and testing systems in Asia after finding a significant amount of substandard drugs in the Greater Mekong Subregion in 2003; and helping the Global Drug Facility to increase the availability of good quality second-line anti-tuberculosis medicines at affordable prices. Through the DQI’s work in Latin America, Africa, and Asia, he said they are “starting to see an impact.” The new PQI program will allow work to expand into Eastern Europe as well.

“This program allows us to finish the job we have started,” Lukulay said.

That’s why news from Ecuador made me do a doubletake.

Last Monday, Ecuadorean President Rafael Correa gave local officials the power to issue compulsory licenses that enable Ecuadorean companies to bypass patents and produce inexpensive versions of various drugs. Correa’s decree did not specify which, or even how many, drugs’ patents could be bypassed. The licenses, issued according to the World Trade Organization’s rules, are intended to expand access to medications and improve public health.

To my surprise, Pfizer (New York), GlaxoSmithKline (GSK, London), Bayer (Leverkusen, Germany), and others reacted to the announcement with equanimity. In a statement, these and several other companies said, “We accept the democratic decision … to use this extraordinary legal measure, observing the rights and responsibilities” laid out in international law. “No legal right of any kind can take precedence over the interests of public health,” they added.

This reaction is 180° from the opposition that Brazil and Thailand faced in 2007 when they used this tactic. The International Federation of Pharmaceutical Manufacturers and Associations criticized Brazil for not collaborating with Merck (Whitehouse Station, NJ) before its government issued a compulsory license for the AIDS treatment Efavirenz. After Thailand issued a compulsory license for Abbott’s (Abbott Park, IL) Kaletra, the company said it would no longer register new drugs for sale in that country.

I could not find statements responding to Correa’s directive on these companies’ websites and I don’t know why they reacted differently than Merck and Abbott did in 2007. Maybe Pfizer, GSK, Bayer, and the other companies coordinated their response to improve their public images. Or maybe their statement reflects a changed attitude about the limits and ethics of patent protection.

Whatever their motivation, these companies’ endorsement of compulsory licenses will likely set a precedent that makes other drugmakers more willing to accept this legal measure. Compulsory licensing is sanctioned and regulated by international governments and trade organizations. I think it can be a valuable tool that saves patients’ lives, and I’m heartened by the thought that Big Pharma might be more tolerant of this measure in the future.

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.

Last month, US Food and Drug Administration Commissioner Margaret Hamburg announced the agency’s six-point plan for tougher enforcement of its policies and regulations as means of protecting public health. The plan, which includes actions like setting postinspection deadlines, speeding the Warning Letter process, and working more closely with FDA’s regulatory partners, was designed to “to prevent harm to the American people,” as Hamburg said in an FDA release. 

The agency has been actively involved in several recent cases involving instances of illegal importation and sales, drug diversion, and misbranding of drug products. FDA’s Office of Criminal Investigations has conducted investigations and partnered with other government offices when necessary.

From the United States Attorney’s Office, District of New Hampshire
On July 27, 2009, Christopher Chase, of Lynn, Massachusetts, was sentenced to three and a half years imprisonment and three years of supervised release for his involvement in an Internet prescription drug scheme that distributed anabolic steroids, human growth hormone (HGH), insulin-like growth factor (IGF-1), and clenbuterol throughout the United States. A two-count indictment charged Chase and two codefendants with conspiracy and money laundering. 

According to the indictment, Chase and his team illegally imported the drugs from overseas, primarily China, marketed them as body-building substances, and sold them without a prescription on various websites. Of course, FDA has not approved anabolic steroids, HGH, or IGF-1 for use in body-building activities, and clenbuterol is not approved for use in humans by FDA. Although some countries have approved it as a prescription-only bronchodilator, clenbuterol is known to be abused by bodybuilders for its weight-loss properties, according the the Department of Justice. The money from the sales of these drugs was sent to various merchant bank accounts that Chase had set up, and then laundered through foreign countries such as China and Moldova.  

FDA’s Office of Criminal Investigations worked with US Immigration and Customs Enforcement, the US Postal Inspection Service, and the Internal Revenue Service, Criminal Investigations office on the case.

From the United States Attorney’s Office, Southern District of Florida
Last month, Arnesto Segredo was convicted of conspiring to divert the prescription HIV drug Serostim (somatropin [rDNA origin] for injection, EMD Serono, Rockland, MA) and Nutropin AQ (somatropin [rDNA origin] injection, Genentech, South San Francisco, CA), which is approved for the treatment of growth hormone deficiency, and one count of causing the diversion of these drugs in interstate commerce.

Segredo used unlicensed California-based suppliers to ship hundreds of boxes of Serostim, and some Nutropin AQ, to him in Miami from 2000–2002. He operated a prescription drug wholesaler that was not licensed to engage in the distribution of prescription drugs in Florida from 2000–2001. Segredo later ran his scheme through Genendo Purchasing Organization, a Miami-based prescription drug wholesaler that became licensed in Florida in July 2001. According to a press release from the US Attorney’s Office, a significant portion of the Serostim originated from California-based AIDS patients who sold their Serostim supplies secured from the Medi-Cal Medicaid program. The drugs were shipped from the California-based unlicensed suppliers to Segredo in Florida.

Sentencing is scheduled for October 23, 2009 in Miami. FDA’s Office of Criminal Investigations conducted the investigation.

From the United States Attorney’s Office, Northern District of New York
In a case involving the misbranding of drugs by physicians, The Plastic Surgery Group (TPSG, Albany, NY) pleaded guilty in early August to one felony count of misbranding drugs, and five physicians, the practice administrator, and the supervisory nurse of TPSG also pleaded guilty to strict-liability misdemeanor misbranding violations. In 2004, TPSG misled patients by injecting them with the unapproved product TRI-toxin (botulinum toxin type A) manufactured by Toxin Research International (Tuscon, AZ) instead of the FDA-approved brand Botox Cosmetic (botulinum toxin type A) manufactured by Allergan (Irvine, CA) patients believed they received. Patients not only believed they were getting Botox injections, but paid Botox prices for the cheaper and more dangerous unapproved drug TRI-toxin that TPSG administered.

TPSG faces a fine of up to $500,000 and an order to pay restitution to about 150 patients, who paid approximately $100,000 for the phony Botox injections. The individual defendants face up to one year in prison and fines of up to $100,000. Sentencing is scheduled to take place on Dec. 10, 2009. FDA’s Office of Criminal Investigations conducted the investigation of this case.

These cases are examples of FDA’s efforts to protect consumers by stemming the flow of illegal or adulterated substances. Increased enforcement of FDA’s regulations, especially in the face of rising of illegal activity concerning prescription drugs online, will help to protect public health. As Hamburg said, “The FDA must be vigilant, the FDA must be strategic, the FDA must be quick, and the FDA must be visible.”

As discussed in PharmTech’s blog, the debate on data exclusivity for biologics was intensified with the release of a Federal Trade Commission (FTC) report earlier this month that said that the 12–14 years of regulatory exclusivity for biologics was too long to promote innovation particularly since innovator-drug firms would likely retain substantial market share after the entry of a follow-on biologic (FOB), according to an FTC press release.

GPhA agreed. “In citing the recent FTC report on biogenerics, the President rejects attempts by the pharmaceutical and biotech industries to needlessly extend market exclusivity provisions to an unprecedented period of 12 to 14 years simply to maintain their monopolies on biopharmaceutical products,” said GPhA President and CEO Kathleen Jaeger, in prepared statement. “The White House and Office of Management and Budget correctly recognize that this exclusivity model will not achieve what should be our shared goal of balancing pharmaceutical innovation and much needed consumer access.”

However, BIO, which represents innovator biotechnology drug companies, said curtailing exclusivity was ill-advised. “We are extremely concerned that the seven years of data exclusivity called for by the administration in the letter points to a risky short cut to biosimilars,” said BIO President and CEO Jim Greenwood in a prepared statement. “We believe this abbreviated period will undermine the incentives necessary for continued biotech research into breakthrough medicines and cures for diseases such as cancer, multiple sclerosis, Alzheimer’s and HIV/AIDS as well as unmet medical needs.”

Whether one sides with GPhA and the White House or with BIO, it is important to consider not just “the end” but “the means.” Part of the argument for limiting exclusivity is that competition in the FOB market would be narrow given the higher barriers of entry (i.e., cost and expertise) compared with competition in the small-molecule generic-drug market. As a result, the FOB market would have fewer suppliers and higher prices.

Although this may be true, the mechanism for addressing anticompetitive concerns in the FOB market is not to circumscribe innovator-drug companies. The concerns raised by the FTC in a still nascent FOB market are not a by-product of anticompetitive practices by innovator-drug companies but result from the market itself. Higher capital costs for producing biologics, limited technical expertise of suppliers in producing biologics, and a lower market return on biologics given the often more specific patient focus of a biopharmceutical are major reasons for the anticipated reduced entry of suppliers in the FOB market. How would limiting innovator-drug companies address these underlying fundamentals? Moreover, given the quality demands on any pharmaceutical product, particularly biologics with their more complex nature compared with small molecules, is it really desirable to create an FOB market that would encourage a multitude of suppliers?

Access to affordable medicines and fair pricing of pharmaceuticals for the consumer and for the companies that produce them is a critical issue for biologics or small-molecule pharmaceutical products, but we need to be careful about the tools of reform. Different policy mechanisms more specific to the actual goal, such as pricing ceilings for drugs or other models in healthcare reform, are more appropriate and should be on the table. These choices will no doubt engender fierce debate as well. But at least we would not be obfuscating the issues and would have a meaningful start to get to the real heart of the matter.

Lavery was found by the court to be a leader and organizer in a scheme in which large quantities of the HIV drug Serostim (somatropin recombinant) were purchased from patients infected with HIV and then reintroduced into the wholesale distribution chain using falsified paperwork. The diverted drugs were sold in various parts of the country to licensed distributors who believed they were purchasing legally supplied drugs.

On Sept. 4, 2007, Lavery pleaded guilty to a 44-count indictment charging him with wire fraud conspiracy and wire fraud, money laundering, conspiracy to engage in unlicensed wholesale distribution of prescription drugs, and false statements in a matter under the jurisdiction of the US Food and Drug Administration.

Lavery ran the distribution scheme with Robert McFadden, who was sentenced on May 19, 2009, to three years of incarceration to be followed by two years of supervised release. McFadden, an attorney in Palm Springs, California, was convicted of conspiracy to launder monetary instruments, conspiracy to commit wire fraud, and conspiracy to engage in unlicensed wholesale distribution of prescription drugs by a US District Court in January 2009. In the scheme, McFadden used his client trust account to launder more than $2.1 million from licensed wholesalers in California and in Milford, New Hampshire.

Also involved in the scheme was Beth Handy of Milford, New Hampshire, who has pleaded guilty to similar charges and awaits sentencing in the US District Court in Concord. Handy, who at the time was a licensed drug wholesaler in New Hampshire, sold diverted Serostim to other prescription drug wholesalers. Handy and Lavery falsified paperwork such as pedigrees, invoices, packing slips, and shipping labels to create the illusion that the Serostim they sold had been obtained legally and was shipped from New Hampshire, when it was actually being shipped from Palm Springs, California. The paperwork was submitted to the Serostim customers and the New Hampshire Board of Pharmacy.

Special agents of the US Food and Drug Administration’s Office of Criminal Investigations, the Health and Human Services’ Office of the Inspector General, and the Internal Revenue Service investigated the case. The case was prosecuted by special assistant US attorney Sarah Hawkins and assistant US attorneys Aixa Maldonado-Quinones and Mark Irish.

Irish said in an interview with PharmTech.com that the “sophisticated” scheme was investigated for the past several years by the three agencies, and that the government dedicated many resources to the case because it greatly affected the integrity of the distribution system of prescription drugs. “We hope this sends a message that if you engage in this kind of diversion, you will end up with a federal prison sentence,” he said.

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.

Two recent reports have touched upon the challenges posed by mutating and resistant viruses, making vaccine formulation and development difficult. Scientists at the University of Alabama at Birmingham (UAB) have identified at least 14 “escape mutations” of HIV. These adaptations help keep the virus alive even after it interacts with the immunity molecules that usually affect it. In addition, influenza viruses continue to pose new challenges. A recent study shows that during the 2007-2008 influenza season, the resistance of the influenza A(H1N1) virus to the drug oseltamivir actually increased for the first time worldwide. Scientists are now predicting the resistance will increase for the 2008-2009 flu season, still in progress.

There is some good news on the vaccine front, however. With the help of genetically modified organisms and rapamycin (used in organ transplantation), researchers at The University of Texas Health Science Center in Houston have been able to boost the efficacy of the only approved tuberculosis vaccine for humans. The team was able to block the “evasive mechanisms” of Bacille Calmette-Guerin (BCG), which does not protect against tuberculosis completely. BCG evades immune-stimulating mechanisms such as antigens (molecular components of the bacteria); but the use of rapamycin allows the antigens to enter certain pathways that would allow the immune system to recognize them.

The challenge is a win–win situation, and it’s good news considering some of the recent frustrations and disappointments in the world of AIDS vaccine research. Last spring, The Independent reported an overall pessimistic view held by the research community in its story, “Is it time to give up the search for an AIDS vaccine?” The failure of Merck’s vaccine trial in late 2007 was a major setback to the field, and the announcement of Roche’s halt of its HIV research program last July didn’t help morale.

In a May 2008 column, Requiem for a Vaccine, PharmTech Editor-in-Chief Michelle Hoffman discussed the scientific community’s distress and its strategy to get back to basic research in hopes of finding new answers. This plan was recently echoed by Luc Montagnier, co-winner of the 2008 Nobel Prize for Medicine and the co-discoverer of the HIV virus, when he joined the advisory board of the biotechnology company Viral Genetics. Montagnier said of his appointment last month:

“While some preventive candidate vaccines failed to protect against HIV infection, and since there is no treatment able to cure the disease, it is important to come back to basic research and to explore new ways of research and treatment such as those explored by Viral Genetics. This is why I joined the advisory board of this company.”

The year ended with announcements of progress of treatments and vaccines on the 20th anniversary of World AIDS Day, Dec. 1, 2008. GeoVax Labs outlined the launch of Phase II clinical trials of its vaccine at 12 sites involving 225 patients. The trials are a collaboration with the National Institutes of Health and the HIV Vaccine Trials Network. Also, a report released by the Pharmaceutical Research and Manufacturers of America (PhRMA) found there are 109 medicines currently in development for HIV/AIDS, 29 of them vaccines. Moving beyond the setbacks and pessimism of 2008, the World AIDS Day announcements bring new hope for fighting the disease.