Erik Greb

Pharmaceutical companies that face dwindling new-drug pipelines are pursuing new delivery methods for their drug products. One strategy is to develop respiratory delivery techniques for drugs that are now administered by injection. Pfizer's (New York) "Exubera" product and Novo Nordisk's (Bagsvaerd, Denmark) "AERx" treatment were high-profile examples of this gambit. Although these companies stopped supporting their new drugs after they failed to meet market expectations, researchers and manufacturers still consider respiratory delivery of biologicals a viable option. 

ART DIRECTION: MELISSA MCEVOY. BACKGROUND/SPACESHIP: CHAD BAKER/GETTY IMAGES. ASTRONAUTS: PHILIP LAURELL/GETTY IMAGES 

When Pfizer and its development partner Nektar Therapeutics (San Carlos, CA) introduced the Exubera inhaled-insulin product in summer 2006, respiratory drug delivery enjoyed a moment in the spotlight. No company had manufactured an inhaled insulin before, and Exubera was projected as a potential blockbuster. 

John Patton, chief scientific officer and cofounder of Nektar, says that Exubera is a friendly option for patients who otherwise would postpone taking injected insulin for years. Exubera thus can reduce premature death and the early advancement of diabetes sequelae that patients would otherwise suffer, according to Patton. Patients also appreciate the fact that Exubera is the first room-temperature stable insulin formulation. 

The product has therapeutic benefits as well. "Exubera's onset is just as fast as that of monomeric insulin, yet it has a longer release profile and lasts longer," according to Patton. He notes that Exubera patients' postprandial and fasting-plasma glucose levels were lower and closer to normal than those of patients who injected insulin. 

Fluorescence-dye solution (above) and microscopy imaging (left) of fluorescence-labeled pulmonary "CaP" insulin parti-cles from BioSante. (PHOTOS COURTESY OF BIOSANTE PHARMACEUTICALS) 

Robert E. Sievers, professor of chemistry at the University of Colorado and CEO of Aktiv-Dry (Boulder, CO), says Exubera was "a scientific 

" He adds that the inhaler that delivered the drug was "a wonderful mechanical apparatus." Aktiv-Dry uses Exubera as a standard against which to measure its own respiratory drug-delivery devices. "That speaks a lot for it," Sievers observes. "It says that Exubera works, both the powder and the inhaler." 

Despite Pfizer's best efforts, Exubera's sales were disappointing, and in Oct. 2007, Pfizer decided to stop investing in Exubera. In a company press release, Jeff Kindler, Pfizer's chairman and CEO, said that Exubera had "failed to gain the acceptance of patients and physicians." 

What went wrong? Richard Dalby, professor of pharmaceutical sciences at the University of Maryland, notes that Exubera's device is 16 cm tall, while pressurized metered-dose inhalers are generally 9 cm tall. Exubera's size might have been off-putting to patients and healthcare workers more familiar with syringes and injection pens. 

"A larger problem was the realization that most patients would require concomitant administration of a long-acting insulin, which was only available by injection," Dalby observes. "In effect, Exubera added to the complexity of a diabetic's drug regimen rather than simplifying it or making it less painful." 

Stephen M. Simes, president and CEO of specialty drug company BioSante Pharmaceuticals (Lincolnshire, IL) makes a similar point, noting that Exubera was impractical because it required an "almost one-for-one replacement of injection with inhalation." 

"Doctors didn't think it brought the patient that much additional advantage," Sievers says. Physicians decided it would be easier to continue therapeutic regimens that were familiar to patients, rather than encourage something that was new and, in their view, unnecessary. 

A model demonstrates the use of Aktiv-Drys "PuffHaler" inhalation device. (PHOTO COURTESY OF AKTIV-DRY) 

Although Pfizer abandoned Exubera, and Novo Nordisk discontinued its development of AERx, respiratory delivery of biological therapies is still a live prospect. "The possibility of commercializing inhalation of long-acting insulin or combinations of long- and short-acting insulin exists," says Dalby. He adds that Exubera benefited from "a well-funded and sustained research effort that has allowed us to learn more about the strengths and weakness of inhaled biomolecules." Dalby notes that Pfizer's experience opens the door for manufacturers to develop respiratory delivery of other biologicals, particularly those with a wide therapeutic index. 

Pfizer itself has apparently not abandoned its quest for inhaled insulin. In Feb. 2008, Reuters reported that Pfizer would invest EUR 130 million ($189 million) to build a facility that formulates and manufactures inhaled drugs. Pfizer chose to construct the unit at its Amboise, France, production plant. 

In a statement on Oct. 18, 2007, Kindler said, "We remain committed to investing significant resources in the development of new and innovative medicines to manage diabetes, including monitoring inhalation technologies and other innovative delivery systems for insulin and other medicines." 

Nektar is working on improvements to Exubera. The company simplified its insulin formulation by removing some excipients, Patton remarks. The new formulation can be delivered by a device "that you can hide in the palm of your hand," he says. Unlike the old device, the new inhaler is breath-activated. It "has a trigger that won't release air until you've achieved a certain pressure," Patton explains. He adds that the new device is less complicated and provides simpler dosing than the old device. 

After discontinuing development of its fast-acting AERx medicine, Novo Nordisk decided to refocus its inhaled-insulin program. In a Jan. 14, 2008 press release, Lars Rebien Sørensen, the company's president and CEO, said, "We have concluded that fast-acting inhaled insulin in the form it is known today is unlikely to offer significant clinical or convenience benefits over injections of modern insulin." 

The company announced it would increase its research and development activities to create inhalation systems for long-acting formulations of insulin and glucagon-like peptide-1 (GLP-1), which increases insulin secretion from the pancreas. An inhaled, long-acting insulin would eliminate the need for injections, which Exubera failed to do. 

BioSante is pursuing the same goal as Novo Nordisk. Simes says BioSante has developed formulations for the delivery of long-acting proteins into the lungs. The company cooperated with the University of North Carolina on its "CaP" project to prolong the delivery and biologic effect of insulin (as the model protein) into the lungs. BioSante is now looking for a development partner for insulin as well as other proteins. 

"The CaP approach uses calcium phosphate particles as the delivery system for insulin and other proteins," according to Simes. He thinks the approach has potential for controlled drug release. The technique would be easy to administer, compared with injections, and most likely acceptable to prescribers and patients, according to BioSante. 

The CaP protein system can be delivered as a powder, which would enable the use of an inhaler. In contrast to Exubera, Simes explains, "CaP should result in better bioavailability, less frequent dosing, and a lower amount of protein per dose." 

Alfred Mann, CEO of MannKind (Valencia, CA), expresses confidence that his company's "Technosphere Insulin" will succeed. Technosphere Insulin is a microparticle powder made from fumaryl diketopiperazine and insulin. A patient loads a powder-filled cartridge into the device and inhales to obtain a dose of insulin. The powder particles have an average diameter of 2 μm and a highly porous surface topography. The particles penetrate deep into the lungs. When they contact the lung surface, they instantly dissolve and release the insulin molecules in a monomer form. Technosphere Insulin is the only inhaled insulin that contains insulin monomer, the form that can readily be used by the body, according to MannKind. 

Unlike Exubera, Technosphere Insulin has advantages over rapid-acting insulin analogs, MannKind says. The benefits include a reduction in postprandial glucose excursions, comparable levels of glucose control compared with HbA1c (which is considered the standard measure of a diabetes drug's effectiveness), and a lower risk of hypoglycemia. 

Pharmaceutical companies would not continue their inhaled-insulin programs unless respiratory delivery provided a tangible benefit for patients and made economic sense. But before inhalable insulin formulations were developed, aerosols were used to treat respiratory diseases such as asthma, cystic fibrosis, and chronic obstructive pulmonary disease. Drugs for these diseases remain the dominant segment of the respiratory-delivery market. 

Patton says that respiratory delivery is a good option for treating chronic respiratory conditions. He notes that at least 40 inhalation drugs have been approved, Genentech's (South San Francisco, CA) "Pulmozyme" among them, and they are considered relatively safe. "Pulmozyme has proven to be a quite safe protein with chronic use-in sick lungs-over a decade," Patton remarks (1). 

Genentech developed the Pulmozyme biological as an inhalation solution to manage cystic fibrosis. The US Food and Drug Administration approved the drug product in 1993. 

Companies are seeking new inhalation treatments for cystic fibrosis. For example, BioSante is examining the possibility of using its CaP system for respiratory delivery of α

 -antitrypsin. This medicine for cystic fibrosis could also be used to treat emphysema and venous thromboembolism, according to the company. 

Scientists have investigated respiratory-delivery methods for drugs that manage pulmonary hypertension (PH), including iloprost. In Dec. 2004, FDA approved Actelion Pharmaceuticals's (Allschwil, Switzerland) "Ventavis" iloprost inhalation solution. In Nov. 2007, United Therapeutics (Silver Spring, MD) announced positive results of its Phase III trial of "Viveta," an inhaled formulation of treprostinil that treats PH. 

Drugs that treat tuberculosis (TB) cannot be given at high doses because high systemic exposure causes toxic side effects. But one can deliver these drugs directly to the lungs at much lower doses using an inhaler. This technique would have a better therapeutic effect than a pill or syringe would. It would also result in fewer toxic side effects. "Pulmonary delivery is a much better alternative than injection to treat local conditions," Simes says. 

Researchers are developing inhalable vaccines against TB, remarks Dalby. In 2007, the 

 reported that a Harvard research team developed a spray-drying method to preserve and deliver the Bacillus Calmette-Guérin (BCG) TB vaccine. This spray-drying technique could lead to aerosol delivery of BCG. 

Sievers observes that some therapies such as small interfering RNA (siRNA) drugs are only effective if they can be delivered into cells at the site of infection. Recent evidence suggests that "the administration of siRNAs in aerosol form works for certain applications where injections were less effective," he says. Pharmaceutical companies "are bound to be looking at siRNAs because they're such a wonderful strategy." siRNAs could be used to treat respiratory syncytial virus (RSV) infection and diseases such as cancer. 

Alnylam (Cambridge, MA) is developing ALN-RSV01, a siRNA, for the treatment of RSV. In Jan. 2008, the company announced study results showing that ALN-RSV01 was safe, well tolerated, and demonstrated statistically significant antiviral activity. Alnylam will use its "Direct RNAi" approach to deliver the drug directly to the lungs to neutralize the virus. 

Formulating drugs for pulmonary administration presents challenges, however. Although scientists know the lung absorbs biologic drugs that have a wide range of molecular weights, lipophilicities, and polarities, "our ability to predict the mechanism, rate, and extent of absorption is at an early stage," Dalby cautions. 

Delivering inhaled formulations to the lung may cause local toxic effects such as edema, cell injury, or altered tissue defenses. Propellents, preservatives, or carriers such as sulfites may also harm the body. 

Patton acknowledges that safety is always a concern for any new form of drug delivery, but he argues that it can be managed. "The lung has a great capacity for handling foreign material," he says. Delivering grams of drug would be unwise, Patton admits, but "for most biologicals and other drugs, that's usually not a problem" because they would be given in microgram to low milligram doses." 

Respiratory delivery moves beyond the lung

Success in treating respiratory diseases with inhaled formulations inspired research into expanding respiratory delivery to treat systemic diseases. "All the scientific evidence to date indicates that the systemic bioavailability via the respiratory route is vastly higher than noninvasive or nondisruptive percutaneous absorption," according to Igor Gonda, CEO of Aradigm (Hayward, CA). 

Simes agrees. "If the drug is safe and can escape the lungs' natural clearance mechanisms until their therapeutic payload has been delivered, it can achieve equivalent or higher bioavailability than pecutaneous injection." Respiratory delivery is "particularly useful for the delivery of drugs to distant target organs through the circulatory system," Simes adds. 

"The idea of systemic delivery of biomolecules and the development of a sophisticated, highly reproducible inhalation device and formulation to administer them were and remain innovative," according to Dalby. 

As companies continue their pursuit of inhalable treatments for diabetes and respiratory diseases, researchers investigate other diseases that could potentially be managed through respiratory drug delivery. BioSante believes drugs that could be delivered through the lungs include the protein human Factor IX for hemophilia and Interferon alpha-2b for chronic hepatitis B. 

A 2007 study shows that inhaled drug delivery can effectively combat measles, Sievers says. Dilraj and his colleagues demonstrated that children revaccinated with Edmonston–Zagreb wet-mist aerosol had a stronger and longer-lasting antibody response six years later than those revaccinated subcutaneously (2). Wet-aerosol vaccination, Sievers observes, could thus provide durable protection against this disease. 

The World Health Organization and the Serum Institute of India are directing Phase I clinical studies with a wet-mist aerosol measles vaccine in India. 

Sievers adds that DelSite (Irving, TX) recently developed a flu vaccine in gel form for intranasal delivery. "If you ship a powder around the world and store it, you have to ship high-purity water for injection along to reconstitute it," he explains. Although powders and liquid suspensions are susceptible to contamination and decomposition, dry powders are generally more stable than liquid suspensions. DelSite's formulation is "easier to store and less susceptible to bacterial contamination than a liquid suspension would be," he says. 

Articles

Companies continue to develop inhaled insulin and other drugs, despite the problems that Pfizer's "Exubera" experienced.

Inhalable Drugs on the Launch Pad: Will They Take Off?

Pfizer's (New York) "Exubera" is only a recent example of a biological drug that was succesfully formulated for respiratory administration. In 1993, the USFood and Drug Administration approved Genentech's (South San Francisco, CA) "Pulmozyme"(inhalable dornase alfa), a biological drug for the treatment of cystic fibrosis. 

What characteristics make a drug suitable for respiratory delivery? First, a drug must be stable in aqueous or powder formulations to be aerosolized. In addition, powders should be free-flowing so they do not aggregate and prevent consistent delivery, observes Robert E. Sievers, professor of chemistry at the University of Colorado and CEO of Aktiv-Dry (Boulder, CO). 

Proteins, peptides, and monoclonal antibodies are good choices for inhaled delivery, according to Stephen M. Simes, president and CEO of specialty drug company BioSante Pharmaceuticals (Lincolnshire, IL). Currently these active ingredients can only be delivered through subcutaneous or intravenous routes. The high permeability of the alveolar epithelium makes pulmonary delivery of large molecules more beneficial than administration via injection, Simes says. 

Claims that high molecular weight proteins would be hard to deliver to the lungs make Sievers skeptical. "Maybe, and maybe not," he says, adding that various strategies for the respiratory delivery of large proteins are under investigation. "In gene therapy," he explains, "they use tricks to get things into humans that the human system is normally arranged to defend itself against." 

"Clearly, antibody-sized drugs can be delivered through the airways," notes John Patton, chief scientific officer and cofounder of Nektar Therapeutics (San Carlos, CA). He observes that Syntonix Pharmaceuticals (Waltham, MA) used an approach similar to PEGylation to deliver large molecules to the lungs. The company attached cytokines to their drug to transport it across the pulmonary epithelium. The technique resulted in good absorption and prolonged activity, Patton says.  

Formulators must pay attention to particle size, Sievers argues, because that determines whether a drug is deposited in the nasal passages, the throat, or the lungs. Manufacturers must aim for a different target, depending upon the formulation. Drugs that can be formulated as 1–4-μm particles, for example, generally are good candidates for pulmonary delivery. 

Low molecular weight hydrophobic molecules are also appropriate. These molecules are absorbed more rapidly and have better bioavailability than hydrophilic molecules. Molecules that are too hydrophobic, however, have low solubility and delayed action. Charge-masking can help formulators deliver charged, low-molecular weight molecules. 

Bioavailability isn't a crucial concern for inhaled drugs providing systemic delivery unless the drugs are expensive, according to Igor Gonda, CEO of Aradigm (Hayward, CA). Dose size and therapeutic index are, however. Reproducibility of delivery is important for efficacy and safety if the drug has a relatively narrow therapeutic index. 

Richard Dalby, professor of pharmaceutical sciences at the University of Maryland, agrees. "A small effective dose, wide therapeutic index, and evidence for complete absorption following respiratory delivery make a candidate scientifically promising," he says. 

For more about respiratory delivery of biological drugs, see "

Inhalable Drugs on the Launch Pad:Will They Take Off?

What makes a drug ripe for respiratory delivery?

Journey to the Center of the Lung

 
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Outsourcing clinical-trial materials (CTM) is strong and growing. Because of significant cost pressures and the globalization of clinical research activities, pharmaceutical companies are hiring contract manufacturing organzations (CMOs) to provide many services, including CTM production. In response to the growing demand, CMOs are expanding their capacity both domestically and internationally. 

Early-stage pipeline growth spurs demand for CTM services

Demand for CTM services stems from robust drug pipelines. The number of Phase I candidates has grown by 60% in the past five years, and the number of Phase II candidates by 30% (1). Approximately 75% of these candidates originated at small and mid-sized pharmaceutical companies (2). The Pharmaceutical Research and Manufacturers of America reports 1264 drugs were in Phase I development, and 1171 drugs were in Phase II development as of December 11, 2007. 

As early-stage pipelines increase, pharmaceutical companies are increasing their outsourcing of CTM supplies. The largest shift in demand for clinical supplies is occurring within the mid-sized to large pharmaceutical companies, observes Scott Houlton, chief operating officer of Aptuit (Greenwich, CT), a contract drug-development services company. Large and mid-sized companies historically outsourced only a small portion of their work, he remarks, but they are changing their approach. This segment of the market is beginning to strategically hire two or three key partners for certain projects. 

Others confirm the trend toward multiple-vendor outsourcing. "Some sponsor companies may hire more than one contractor to develop the same drug product for the same phase," says Maureen Spataro, founder and president of the North Carolina-based consulting firm Spataro and Associates. "This way, they benefit from having two sets of scientists working on their CTM." Hiring several CMOs for the same project increases the chances that it will be completed successfully, she adds. 

Another approach, according to Spataro, is to hire several contractors to develop different dosage forms or different release profiles for one product. "The ultimate goal is to save time," she says. "By contracting to multiple vendors, development efforts can be achieved on a parallel path. If one company's prototype fails along the way, there is a possibility that the other may succeed." 

Phil Meeks, chief executive officer of the CMO Azopharma (Miramar, FL) agrees that meager late-stage pipelines are spurring increased outsourcing. Pharmaceutical companies are now trying to get more candidates into clinical trials, he says. "If companies have capital," he adds, "they'll outsource to achieve more at once." 

Aptuit's clinical packaging and logistics facility in Bathgate, United Kingdom. (IMAGE IS COURTESY OF APTUIT) 

Nailesh Bhatt, managing director of the New Jersey-based consulting and advisory firm Proximare, says, "Outsourcing has definitely increased by the large companies." Big pharmaceutical companies are deciding to focus on their core competencies. These companies are now more likely to ask CMOs to perform services for which they themselves have less expertise or ability. Spataro concurs, commenting that large pharmaceutical companies are now looking to contractors for CTM because they have made a strategic decision to outsource and focus on their core competencies. Manufacturing CTM "is not something that everybody's capable of handling," says Bhatt. 

Cost pressures and Big Pharma's recent restructuring activities are creating the conditions for increased outsourcing. A reorganization plan that Pfizer (New York) announced in January 2007 reflects this trend. The company said it would cut 10,000 jobs and close several plants to save approximately $2 billion by the end of 2008. Among the plants to be closed are Pfizer's facilities in Ann Arbor, Michigan, where the company prepares clinical supplies. Pfizer said it would increase outsourcing to reduce expenses. 

But restructuring is not the only reason that large and mid-sized companies outsource CTM. Anthony Moult, director of global clinical-trials supplies at UCB Pharm (Braine-l'Alleud, Belgium), notes that the primary reason his company outsources a given project is usually that it cannot be done in-house. "For example," Moult explains, "we don't really have a clinical-trials supplies capability for the storage and distribution of large volumes of refrigerated products." UCB generally looks to vendors to supply these services. 

"Our internal approach," he adds, "is if we haven't got the technology, we contract it out. If we have internal capacity and, looking three, six, or twelve months out, we would be overloaded by our current plans, then we would look to strategically and tactically outsource the packaging and distribution of those materials." 

Small pharmaceutical companies must outsource CTM services when they lack capacity and expertise. They "may have limited experience with drug-development activities, especially CTM," Spataro observes. "They have limited internal operations," she says, "and therefore must rely on contract providers for an array of product-development services such as formulation development and clinical-trial material manufacturing, packaging, and distribution." 

CMOs agree that small and emerging companies are an important part of the outsourcing equation for CTM supplies. Meeks says most of Azopharma's CTM projects now come from small and mid-sized companies. Virtual companies must outsource many projects because they don't have the internal operations to complete them, he observes. 

Aptuit continues to receive a steady number of contracts from small and emerging pharmaceutical companies, which are an important customer base for the company, according to Houlton.  

 Still, Houlton stresses that Aptuit "works with customers of all sizes—from virtual to large pharmaceutical companies—to help them advance their compounds from discovery to launch." 

Outsourcing CTM is not a strategy that is limited to one segment of the pharmaceutical industry. Bhatt says, "All the players are outsourcing CTM. More and more, companies must fail faster and in a cheaper manner, so the [outsourcing] activity is by everybody." 

Responding to increased demand, CMOs are expanding their CTM-supply capabilities. In January 2007, DSM Pharmaceuticals (Parsippany, NJ) added a CTM manufacturing suite to its sterile parenteral manufacturing facility in Greenville, North Carolina. The suite manufactures large- and small-molecule liquid and lyophilized products for Phase I–III clinical trials. In November 2007, DSM added formulation development and clinical-trial manufacturing for solid dosage forms to its service offerings. 

In April 2007, AAIPharma (Wilmington, NC) completed $2 million worth of upgrades to its parenteral manufacturing facility in Charleston, South Carolina, and its sterile-product release operation in Wilmington. The improvements were designed to increase capacity and ensure compliance with European Union aseptic-processing and testing guidelines. Lee Karras, senior vice-president of North American pharmaceutical operations, said that the upgrades were "of particular importance to customers who wish to conduct clinical trials in the EU." The EU's Clinical Trials Directive harmonizes the conduct of clinical trials and affects the manufacture and importation of CTM into the region. 

Bilcare Global Clinical Supplies (Pune, India) opened five primary packaging rooms at its Phoenixville, Pennsylvania, facility in November 2007. The company planned to achieve the next phase of upgrades during the fourth quarter of 2007 by creating five additional primary rooms. The expansion would give Bilcare 10 primary and 16 secondary packaging rooms within its 153,000-ft

In addition, Bilcare is investing £11 million ($23 million) to establish a new clinical-supplies facility in Wales. This facility will replace the existing clinical-supplies facility Bilcare acquired in 2006. 

In November 2007, Catalent Pharma Solutions (Somerset, NJ) added a Phase I sterile vial-filling suite to its facility in Research Triangle Park, North Carolina. The suite complements the clinical-manufacturing capabilities at Catalent's North Raleigh, North Carolina facility. 

Meeks says that Azopharma made four major acquisitions during 2007. The company gained facilities for preclinical services, inhalation development, synthetic chemistry, and manufacturing during the year. "These added capabilities, coupled with our existing expertise, enable Azopharma to truly offer total product development, from discovery to manufacturing, with all the development activities in between." 

In June 2007, Metrics (Greenville, NC) initiated a 47,000-ft

  expansion of its clinical-batch manufacturing and commercial-production capabilities. The expanded facility is scheduled for completion in April 2008 and will contain approximately 9000 ft

  of pharmaceutical manufacturing space, and approximately 7800 ft

CMOs in India, China, and Singapore are gaining prominence as globalization plays an increasingly important role in the pharmaceutical industry. "More and more pharmaceutical and biotechnology companies are doing their trials in those countries," Bhatt explains. Conducting a clinical trial in China, India, or other parts of Asia, for example, requires a company "to have a storage facility, a manufacturing facility, logistics, or project-management capability in that region," he adds. 

As drugmakers conduct more clinical trials in Asia, CMOs are responding to meet clients' needs. Some Asian CTM providers that previously served only their local markets now work for multinational pharmaceutical companies, Bhatt notes. These CMOs are familiar with the local infrastructure and supply chain, and they have the local expertise that companies from outside the region require. Increased demand also has "pushed companies such as Thermo Fisher to move into Singapore, India, or China in an aggressive manner," notes Bhatt. 

For example, in October 2007, Thermo Fisher Scientific (Waltham, MA) broke ground on a $17-million facility in Ahmadabad, India. The facility will package and oversee the global distribution and logistics management of pharmaceutical samples for clinical-trial patients around the world. Thermo plans to open the facility in spring 2008. 

Several other companies are building or improving plants in Asia. In June 2007, Aptuit teamed with Laurus Labs (Hyderabad, India), a provider of contract research and manufacturing services, to form Aptuit Laurus. The new company is headquartered in Hyderabad, India. Aptuit plans to invest roughly $100 million during the next several years to increase Aptuit Laurus's development, manufacturing, and informatics capabilities. The expansion includes the addition of development services such as formulation and analytical-testing services and clinical GMP packaging and logistics. "Our expansion into India, combined with our new packaging facilities currently under development in the US and Europe, will nearly double our capacity over the next 18 months," Houlton says. 

Development activities are a large part of Aptuit Laurus's work, according to Houlton. "We expect to further our growth in India with expanded CTM services at Aptuit Laurus." In addition, Aptuit will also produce large commercial volumes of APIs and finished product in India. 

Aptuit has also been active elsewhere in Asia. "Our clinical packaging and logistics operation in Singapore doubled over the past two years," remarks Houlton. Aptuit's expansions in Asia will continue. "We are looking to grow into a new facility in Singapore that will allow us to double or triple our CTM supplies business again," he says. 

According to Bhatt, China, India, and Singapore are the main countries to benefit from the globalization of outsourcing. Because companies can raise or borrow money relatively cheaply in those countries, he explains, "it's become very attractive to grow inorganically through mergers, acquisitions, and joint ventures and to provide services to global companies on the value propositions of convenience, cost, and certainly quality products or quality service. And that's happening more and more." 

Referring to the growing number of clinical trials that pharmaceutical companies are conducting overseas, Bhatt says, "The fact that India, China, Russia, and other countries are being exploited requires clinical-trial supplies to be [available] in a global marketplace. Why would Fisher go and invest $17 million in India if none of their customers were conducting any trials in India or China?" 

In addition, Bhatt notes that companies based in China, India, and Singapore are buying small contract research organizations (CROs) and clinical-trials companies in the US and Europe. He cites Jubilant Organosys's (Uttar Pradesh, India) purchase of Target Research (Berkeley Heights, NJ) and Manipal AcuNova's (Bangalore, India) purchase of Ecron (Frankfurt, Germany). These Asian companies are seeking to increase their size and influence, he says. 

The growth of the offshore outsourcing of CTM projects brings new responsibilities to pharmaceutical companies. Clients must familiarize themselves with the working environment in the CMO's country. They must examine the supply chain, infrastructure, and patient population, among other things. According to Bhatt, companies will have to cooperate with their partners to analyze all the factors that will ensure success. "A great deal of planning, a great deal of strategizing, both at a high level and at a tactical level, is going to be required," he comments. 

The infrastructure in Asia (especially in India, China, and Singapore) for conducting clinical trials and producing CTM deserves particular attention, in Bhatt's opinion. Companies must work to ensure that the product gets to the patients in a safe and timely manner. They must be certain that CTM can be delivered without jeopardizing its temperature or quality. "These are major issues in these countries," Bhatt cautions. 

On the other hand, the obstacles may not be as daunting as they seem. Bhatt says Indian and Chinese clinical trials usually are conducted at certain capable hospitals. Companies don't conduct trials in remote places reached by poor roads or unreliable transportation. Still, Bhatt repeats that drugmakers must plan to ensure that they "choose the right locations and the right partners."  

Spataro remarks that, in addition to new responsibilities, globalized CTM outsourcing will bring benefits to pharmaceutical companies. Working with companies in China and India will give sponsor companies "more cost-effective options, which will result in lower research and development costs," she says. As demand for outsourced CTM increases, more contract companies will likely emerge in Asia, Spataro predicts. 

The corollary is that the growing number of international CTM providers will compete with US-based CTM manufacturers. Although this might not be good news for American CMOs, it could be a boon for pharmaceutical companies. Global competition might result in lower costs, improved customer service, and faster turnaround times among service providers, according to Spataro.   

Although Bhatt claims that outsourcing CTM offshore, particularly to Asia, is "increasing dramatically," Meeks is skeptical. Offshore outsourcing has had no effect on Azopharma's business, he says. Furthermore, the pharmaceutical market has not embraced this strategy, in Meeks's opinion. "I'm not sure the expertise is out there," he says. 

Spataro agrees that some drugmakers are justifiably cautious about hiring international contractors. She says that even if an Asian CMO, for example, has highly educated employees, it still might not have expertise in CTM preparation or compliance with GMPs. "With the recent news of safety concerns about products made overseas, sponsors must be vigilant," she warns.  

Houlton sounds a more optimistic note. "The workforce in India and China is improving steadily," he says. "In addition, the large concentration of patient populations in Asia means that many clinical supplies needed will be dosed in that region." 

The rise in CTM outsourcing doesn't show signs of abating anytime soon. "This is a natural progression that's taking place," according to Bhatt. Meeks notes that more pharmaceutical companies hired contract CTM providers in 2007 than in 2006, and he expects the increase to continue for the next three years. 

Spataro concurs and adds, "Offshore outsourcing of CTM will continue to grow." What could change, however, is what drugmakers expect from CTM providers. Although many companies now look to contractors to offer more cost-effective services, "there will be an increased demand for speed," she predicts.  

The outsourcing of clinical-trial materials grows as pharmaceutical companies adapt to a changing market.

Outsourcing Clinical-Trial Materials Heats Up

So you've decided to hire a contract manufacturing organization (CMO) to produce your clinical-trial materials (CTM). Or you've just signed a deal to provide your services to a top-tier pharmaceutical company. But how do you ensure that the project goes smoothly? Which factors will guarantee that the job is completed successfully? CMOs, pharmaceutical companies, and consultants offered 

All sides agree that accurate and timely communication is a big requirement for a successful outsourcing relationship. "Transparency is key in building good information flow," according to Scott Houlton, chief operating officer of Aptuit (Greenwich, CT), a contract drug-development services company. Partners must be readily available to answer questions and offer details about the work at hand. This way, CMOs are sure to understand the project's specifications, and pharmaceutical companies will know about problems that arise. 

"Another key," Houlton adds, "is to have consistent, ongoing work so that the communication stays fresh." Sharing one major project or many small projects forces sponsors and clients to exchange information regularly. Regular contact helps both parties achieve goals and keeps everyone updated about the project's status. 

In addition, a successful outsourcing partnership requires a great deal of strategic planning, according to Nailesh Bhatt, managing director of the consulting and advisory firm Proximare (Princeton, NJ). Outsourcing relationships are evolving to the point that pharmaceutical companies are "actually talking about tactical strategies with each of the partners," Bhatt comments. Companies are "getting extremely granular," he continues. They might ask a CMO whether it would manufacture their product locally or overseas. They could ask how the CMO's strategy will affect timelines, cost, and product quality. Suppliers are realizing that they must have answers for these questions, Bhatt observes. 

Houlton agrees that partners must join to develop a strategy for the project. They should spend time "planning for success rather than reacting to last-minute changes," he says. 

Maureen Spataro, founder and president of the consulting firm Spataro and Associates (Wilmington, NC), specifies the kind of planning that contractors and their clients must perform. She says the parties should establish master agreements that detail the "clearly defined deliverables" for which the provider and sponsor are responsible. 

A plan must also incorporate realistic timelines that both sides agree to, Spataro continues. Establishing deadlines and sticking to them is crucial, as Anthony Moult, director of global clinical-trials supplies at UCB Pharm (Braine-l'Alleud, Belgium), emphasizes. "We might be happy with a CMO," he remarks, "but if they can't meet our timelines, we go elsewhere." 

But possibly the most important (and most obvious) factor in a positive outsourcing relationship is cooperation. CMOs and pharmaceutical companies must build "cooperative relationships" for their projects to be realized successfully, according to Bhatt. "A great deal of collaboration and a lot of back and forth are involved. It's a consultative approach," he explains. 

"Both parties should have a mutual investment in the success of the relationship," Houlton adds. Spataro echoes this sentiment by noting that each party must meet its commitments. "If either party has too much of the influence," Houlton says, "then the relationship suffers." When an outsourcing relationship has a foundation of trust, he continues, work can proceed efficiently because the sponsor will have less need to verify the outsourcing partner's work. 

What should contractors and their clients bear in mind when they collaborate on a project?

How to Build a Better Outsourcing Relationship

) entered into a collaborative agreement for the development and commercialization of apixaban, an anticoagulant that BMS discovered. The companies are studying apixaban’s ability to prevent and treat various venous and arterial thrombotic conditions, including deep-vein thrombosis and pulmonary embolism.

According to the agreement, Pfizer will pay $250 million upfront to BMS and will fund 60% of development costs from January 1, 2007 onward. BMS will pay the remaining development costs. Pfizer may make as much as $750 million in additional payments to BMS, depending on the achievement of developmental and regulatory milestones. The companies will share responsibility for devising the clinical and marketing strategies for apixaban and will divide commercialization expenses, profits, and losses equally.

BMS and Pfizer also agreed to cooperate on the research, development, and commercialization of a Pfizer discovery program. Among the program’s focuses are advanced preclinical compounds that potentially could treat metabolic disorders such as obesity and diabetes.

Under this agreement, Pfizer will supervise all research and early-stage development activities for the metabolic-disorders program. The companies will conduct Phase III development and commercialization activities jointly. BMS will pay Pfizer $50 million upfront as part of the agreement. Pfizer will assume 60% of development and commercialization expenses, and BMS will assume the remaining portion. The companies will share profits and losses the same way.

New York (Apr. 26)-Bristol-Myers Squibb Company and Pfizer, Inc. entered into a collaborative agreement for the development and commercialization of apixaban, an anticoagulant that BMS discovered.