Angelo DePalma, PhD

	Pain relief has in some ways become, both linguistically and as an endeavor, a metaphor for the larger pharmaceutical industry. Today’s pain market is vibrant and growing, but more focused on risk avoidance or mitigation than on innovation As a consequence, resources that might have been devoted to developing new classes of pain drugs become diverted to making centuries-old painkillers safer and less attractive to abusers.

IMS Health calculated the 2008 US market for prescription pain products at $8.2 billion, up 7.6% over the year before, but up only 8.4% since 2004 (Fig. 1, p. 18). Kalorama Information (New York) estimated the global market for prescription pain products at $26.1 billion in 2006, with drugs comprising 90% of the market’s revenues. According to their report, “The World Market For Pain Management Drugs And Devices,” sales will grow approximately 6% per year through 2010, to $33.2 billion.

	The paucity of new pain drugs has not been for lack of effort. Pfizer’s experience with its Celebrex COX-2 inhibitor illustrates the types of issues facing developers. Approved in 1998, Celebrex became the number-one painkiller in 2004 on sales of $3.3 billion. The following year prescriptions plummeted in the aftermath of the Vioxx debacle, which cast a shadow over all COX-2 agents. Celebrex now carries a “black box” warning to reflect higher cardiovascular risk, but sales have risen, to $2.3 billion in 2008 (per IMS Health data), on the heels of recent non-approvable decisions for competing drugs.

	Pain drugs are conveniently classified into three categories, roughly by mode of action: opioids, the oldest grouping and the one with the highest abuse potential; non-steroidal anti-inflammatory drugs (NSAIDs), which include non-prescription painkillers like ibuprofen as well as prescription-only COX-2 inhibitors; “others,” which work not on nerves or inflammation but on underlying pain mechanisms.

	Another view differentiates drugs that relieve “nociceptive” pain caused by tissue damage or injury from those that act on “neuropathic” pain from diabetes, cancer, and other diseases. The opioids and NSAIDs fall into the first category, while antidepressants, anticonvulsives and topical treatments are used on the latter. “Most pipeline drugs for noiceptive pain consist of reformulations. Neuropathic pain research is where most of the interesting science is going on,” says Terence McManus, PhD, lead analyst for neurology at Datamonitor (London, UK).

	As a class, opioids are a close second, to cholesterol agents, in total prescriptions but only fifteenth in sales revenue, thus the perfect storm of low cost, high availability, and abuse potential.

	Five million Americans reported using opioid drugs recreationally in 2006. Total annual costs of opioid abuse were as high as $400 billion when care, accidents, legal proceedings, law enforcement, incarceration, and lost productivity are taken into account.

	According to the Centers for Disease Control and Prevention, deaths from opioid painkillers have more than tripled since 1999, from 4,000 per year to nearly 14,000 in 2006. Popular agents of abuse include methadone, morphine, oxycodone, hydromorphone, and hydrocodone (the most-prescribed drug in the U.S. with 117 million scripts per year). Half of all overdose deaths involve mixing painkillers with other nervous system agents like tranquilizers.

	The rationale for introducing the non-narcotic COX-2 inhibitors and their predecessors, the NSAIDs, was the promise of aspirin’s benefits without its main side effect, stomach bleeding. NSAIDs and acetaminophen are now largely OTC medicines, although prescription-strength formulations exist as well; the COX-2 inhibitors remain prescription-only.

	OTC status, and the inability of NSAIDs and COX-2 to induce euphoria, lulled consumers into a false sense of safety with these drugs, however. In the mid-2000s COX-2 agents’ troubles arose from their cardiovascular risk but their stomach safety is also an issue. Perhaps more startling is the fact that OTC pain remedies cause 130,000 hospitalizations and 19,000 deaths in the US per year as a result of damage to the liver, kidneys, and heart. As of April, 2009, OTC analgesics carry bold warnings for severe liver damage (Tylenol/acetaminophen) and stomach bleeding (NSAIDs).

	Although pain-drug companies seem preoccupied with reformulating old medicines, particularly the opioids and NSAIDs, innovation is occurring. For example Nucynta (tapentadol; Johnson & Johnson), a centrally-acting pain drug that works through a novel mechanism, was approved in late 2008 but due to its abuse potential was classified as a Schedule II controlled substance in early 2009. Notable Phase III-stage pain drugs include Winston Pharmaceuticals’ Civamide, a topical formulation of the active ingredient in hot pepper, Pfizer’s tanezumab, a protein drug that reduces arthritis pain, and Naproxcinod from NicOX (Sophia Antipolis, France). Naproxcinod belongs to a novel NSAID category, the CINODs (COX-inhibiting nitric oxide donators), which work like COX-2 agents but are gentler on the stomach and do not raise blood pressure.

	Among drugs in the “other” category are the triptans, for treating migraine. Triptans work through novel pain-killing mechanisms and have zero abuse potential, but they do not work for plain vanilla headache or muscle soreness. Merck recently sought a migraine-prevention indication for telcagepant, a new triptan agent, but liver toxicity made the drug unsuitable for long-term preventive use. The company has re-positioned telcagepant as a treatment for acute migraine and plans to apply for marketing approval in 2010.

	Hot on the heels of the Phase III compounds are the ion channel agents, which control the flow of electrically charged chemicals into and out of cells. Icagen (Durham, NC) and Pfizer (New York) are collaborating on sodium-channel pain drugs; Newron (Milan, Italy) has a development-stage calcium channel agent, as do partners Xenoport (Santa Clara, CA) and GlaxoSmithKline (Middlesex, UK). Lead ion-channel agents are currently in Phases I/II.

	Next in line are early-stage agents including the opioid receptor ligands, bradykinin antagonists, mPGES-1 inhibitors, glutamate receptor antagonists, substance P and neurokinin receptor antagonists, P2X2 neuron receptor antagonists, cannabinoids, fish and cone shell toxins, cell and gene therapies.

	Like their colleagues in non-pain areas, developers of analgesics are considering “personalizing” pain drugs by bundling them with tests that identify patients likely to benefit or suffer harm. After FDA rejected Novartis’s (Zurich, Switzerland) Prexige COX-2 agent due to liver toxicity, the company considered resubmitting the drug with a genetic test for predisposition to liver problems. Novartis confirmed last summer that a test was forthcoming, but the drug-diagnostic combination would not be re-submitted for US approval. The personalization route is unlikely to work with opioids because individuals in whom those drugs do not induce euphoria, or who are less prone to addiction, are unlikely to experience pain relief.

	Rightly or wrongly, stakeholders are much more concerned over opioid safety than they are with NSAIDs. The infatuation with addiction, it seems, is itself addictive. Robert Rapoport, MD, who reviews anesthesia and analgesia products at FDA, summarized the problem in an interview in Nature last year. Acknowledging the equilibrium between legitimate pain relief and abuse, noted that “we have made incremental advances but remain far from achieving that balance.”

	The principal strategies that have evolved to curb opioid diversion and misuse are monitoring, post-marketing mandates, law enforcement, and formulation.

	Forty states monitor painkiller use by law, but the numbers of abusers and prescribers are so large only the most egregious are apprehended, and just a small percentage of them actually convicted.

	In 2005, a national bill to monitor the use of prescribed controlled substances passed both houses of Congress unanimously and was signed by President Bush. Critics have warned that as written the law, National All Schedules Prescription Electronic Reporting Act (NASPER), permits government to investigate prescription histories for any reason. For now the issue is moot, however, since Congress has only appropriated $2 million to the program thus far.

	The main reporting mechanism for opioids is the nonprofit Denver-based Researched Abuse, Diversion, and Addiction-Related Surveillance (RADARS) program, initiated in 2002 by Purdue Pharma (Stamford, CT), a manufacturer of opioid pain products. RADARS collects information from poison control centers, treatment programs, surveys, and physicians to create a zip code-level demographic map of abuse. Similarly, the National Addictions Vigilance Intervention and Prevention Program (NAVIPPRO), is a subscription-based risk-management program for high-risk drugs including drugs of abuse.

	RADARS provides more generic information on classes of painkillers, for example extended- vs. immediate-release, where NAVIPPRO homes in on individual brands. NAVIPPRO is managed by Inflexxion (Newton, MA), a firm that consults on pharmacovigilance and health-related behavioral programs.

	Dr. David Kloth, past president and board member of the American Society of Interventional Pain Physicians, believes that if properly funded NASPER could pay for itself many times over. “The savings from prescription monitoring would be astronomical in terms of higher worker productivity, lower law enforcement costs, and ruined lives.”

	Kloth is not as confident in pure enforcement strategies, which he says has been largely ineffective due to the size of the opioid problem and the cost and difficulty of convicting physicians. Despite the existence of pill mills, and widespread opioid tourism involving the rental of buses and airplanes to abuse-friendly jurisdictions, “They don’t go after you unless you’re really, really bad.”

	FDA announced early in 2009 that it was considering a class-wide Risk Evaluation and Mitigation Strategy (REMS) for extended-release opioids. REMS (see Pharmaceutical Commerce, Nov/Dec 2009, p. 1) are post-approval measures to ensure that a product’s benefits continue to outweigh risks. REMS may include any combination of label warnings, education or training for prescribers and dispensers, mandatory registries, individual monitoring, and restricted dispensing.

	Extended release products have turned out to be the proverbial road to hell paved with good intentions. They are safe when used as directed, but abusers easily manipulate extended release formulations to release large doses of opioids.

	A class-wide REMS will not occur for opioids until at least late 2010, as FDA has extended the comment period for implementation by one year (until October 2010). Until then, approvals and post-marketing commitments will be considered on a case-by-case basis. For example, FDA recently issued a REMS for the fentanyl drug Onsolis (Meda Pharmaceuticals). Fentanyl, an opioid 100 times stronger than morphine, is a favorite with abusers. The Onsolis REMS, named FOCUS (Full Ongoing Commitment to User Safety) mandates that prescribers must register the patient by fax and submit the original prescription to an approved, participating pharmacy by courier, which delivers the drug directly to the patient’s home (Pharmaceutical Commerce, July/Aug, 2009, p. 9).

	Like David Kloth, practicing physician Jayson Hymes, MD, director of Conservative Care Specialists (Van Nuys, CA) and a government pain medicine consultant, believes physician education, training and certification are the keys to reducing prescription drug abuse. “More physicians call themselves ‘pain doctors,’ mainly for financial reasons, than have actually been trained as such. Pain medicine is whatever the practitioner says it is. Only when mandatory, official certification becomes the norm will we have enforceable standards.”

	Most opioid postmarketing studies focus on abuse and diversion, not on patients using the drug as directed. “And I don’t see that changing any time soon,” comments Edgar Adams, MD, executive director for epidemiology at Covance (Conshohocken, PA).

	Postmarketing studies on the painkiller Tramadol, in which Dr. Adams was intimately involved, are a model of how such plans can work. Tramadol was approved in the United States in 1994 under the condition that the sponsor undertake postmarketing surveillance. The program, overseen by an Independent Steering Committee of which Dr. Adams was a founder, included an 11,000-patient abuse and addiction-potential study. Through the success of this program, tramadol remains unscheduled everywhere except for two states (Kentucky and Arkansas).

	Covance has developed an opioid monitoring program with two partners (eRx Network (Nashville, TN and Analgesic Research (Needham, MA). The system, which operates within pharmacies’ existing method of communicating with insurers, registers the patient, verifies their opioid-tolerance, and is expected to satisfy REMS requirements for monitoring opioid prescriptions and patients. “The process will add one-tenth of a second to the pharmacy transaction, and will greatly reduce the burden associated with other monitoring methods” says Dr. Adams. Covance has already submitted an NDA employing the new system.

	Formulation strategies for thwarting abuse, which form the core of today’s analgesia “specialty pharma” market, include pharmacologic, physical, and aversion techniques. All go at least one step beyond conventional “modified release.”

	On the pharmacologic front King Pharmaceuticals’ (Bristol, TN) Embeda pain pill includes extended-release morphine formulation, and a “sequestered core” of naltrexone—a second drug that counteracts morphine if abusers try to extract the opioid all at once.

	Analogously, combining NSAIDs with a second agent to protect the stomach may be a viable strategy for reducing serious side effects of OTC painkillers. Horizon Therapeutics (Northbrook, IL) recently completed a large Phase III study on HZT-501, which combines prescription-strength doses of ibuprofen and famotidine. The first drug treats pain, the second reduces stomach acid. Clinical data suggest a 50% decrease in serious stomach ailments in patients taking three to four pills daily.

	Since both active ingredients are generics, Horizon will apply for approval under a 505(b)2 “special protocol assessment.” The big question is what will appear on the drug’s label. Prescription famotidine was approved for treating ulcers, while its OTC brands (e.g. Pepcid) claim to reduce stomach acid. Marketing a “safer ibuprofen” would be a huge feather in Horizon’s cap but only FDA can determine if that claim is valid. Jeff Shermann, MD, Horizon’s chief medical officer, would only say that “our claims will be linked to those in package inserts for prescription doses of both ingredients.”

	Physical barrier strategies include the OraDur formulation, from Durect (Cupertino, CA), which embeds the drug in a highly viscous inert material that is difficult to crush or chew, and from which extracting the active ingredient is extremely difficult. OraDur forms the basis of Remoxy, a sustained-release version of oxycodone jointly developed by Durect and Pain Therapeutics (San Mateo, CA). The sponsors had hoped for an abuse-resistance claim for Remoxy but FDA demurred. Remoxy has now been acquired by King.

	Aversion strategies thwart thrill-seekers with a side effect that negates the euphoria. In partnership with Acura Pharmaceuticals (Palatine, IL), King is developing Acurox, an NDA-stage, immediate-release oxycodone-plus-niacin formulation. Niacin, a B-vitamin, causes an uncomfortable flushing sensation when taken in excess.

	Obtaining expanded safety labeling requires clinical testing specifically designed to demonstrate the new claim, and data analysis supporting the application. From a regulatory standpoint this is mostly uncharted territory, since a claim of lower abuse potential involves consequences that are difficult to quantify. Consequently, it is easy for companies to get in trouble with regulators. “The area is so new that the regulatory guidelines are still undeveloped,” observes Linda Wace, MD, EVP of medical affairs at King.

	Embeda was approved with a REMS due to the product’s “potential for abuse, misuse, overdose, and addiction,” according to an FDA warning letter issued to King on 21 October, 2009. FDA was concerned that King video news releases were “false or misleading” because they minimized Embeda’s risks and strayed too far from the drug’s approved indication.”

	King has gone to extraordinary measures but its success in obtaining expanded safety claims is uncertain. The company routinely subjects its products to extraction and tampering tests, and conducts “abuse liability” studies where recreational drug abuser-subjects rate products blindly. “We ask them how high they get,” Wace says.

	FDA—as would any pain sufferer or healthcare provider&mdash;would like better options for pain management, but until new drugs appear, FDA is trying to make the best of a difficult situation. “Despite increased awareness of the harm resulting from the use of [today’s pain drugs], it is likely that extensive prescribing and use of these drugs will continue,” wrote Janet Woodcock, MD, director of CDER at FDA, in the Nov. 26th issue of the New England Journal of Medicine. “Given this reality, there is a need for more vigorous risk management efforts by FDA and other stakeholders in the health care system.” PC 

Articles

While researchers study new pain-killing pathways, the pharma industry tries drug combinations and alternative-delivery mechanisms By Angelo DePalma, PhD

Safety Issues Dominate Pain Market

	Over the past decade, the slow trickle of oncology drug candidates has become a torrent: Close to 750 new cancer drugs (and new indications for existing agents) are in clinical development, according to PhRMA. 2009 Drug Report, an annual study by Medco, cited targeted oral drugs, combination treatments, personalized medicine, monoclonal antibodies, and expanding indications for existing drugs as leading trends in the oncology drug marketplace.

Medco predicts that new oncology drug approvals will decline in 2009 but rapidly recover thereafter. Oral agents slated for approval in 2010-2011 include Zactima (AstraZeneca’s vandetanib, for lung and breast cancers), axitinib (Pfizer; thyroid), alvocidib (Sanof-Aventis; leukemia, arthritis), motesanib (Amgen; breast, thyroid), and lonafarnib (Schering/Merck; breast). All are small-molecule, oral drugs with novel mechanisms of action. This trend, together with changes in oncology therapy practices, heralds a changed market for delivering cancer care.

	Unlike conventional chemotherapy, which is administered in a doctor’s office or hospital, targeted oral drugs are self-administered in pill or capsule form. Patients find taking pills more convenient than waiting for hours in a clinic for chemotherapy, but what is truly exciting about current-generation drugs is they target biological pathways that cancer cells depend on to survive. Chemo, by contrast, kills all dividing cells, which is the source of side effects like nausea and hair loss. Targeted therapies at their best home in on mechanisms that affect only (or primarily) cancer. 

Cancer is driven by a relatively small number of such pathways that stop working properly. Each general pathway type comes in several varieties, which nature mixes and matches from one cancer patient to the next. Some experts believe that curing cancer, or keeping it at bay for long stretches of time, will entail knocking out multiple pathways with several drugs administered in combination. Determining which pathways are operative, and designing drug cocktails to knock them out, is the future of personalized medicine, says Ken Bloom, MD, a pathologist and chief medical officer at cancer diagnostics firm Clarient (Aliso Viejo, CA). 

	One favorite target pathway is biological signaling, which is carried out by proteins known as kinases. Drugs that disrupt the activity of kinases, known as kinase inhibitors, are among the most successful new oral cancer agents. 

They include the oral drugs Gleevec (Novartis: imatinib), Sutent (Pfizer: sunitinib maleate), Nexavar (Onyx Pharma: sorafenib), Tykerb (GSK: lapatinib), Tarceva (Genentech: erlotinib), and Tasigna (Novartis: nilotinib), all of which are significantly more effective and less toxic than traditional chemotherapy. On the down side these agents work in relatively narrow patient populations. 

Another “pathway” class to watch is the vascular endothelial growth factor (VEGF) inhibitors, which work by slowing the formation of blood vessels that feed tumors. Genentech’s Avastin (bevacizumab), arguably the most successful VEGF agent, is an injected biologic for treating advanced cancers of the colon, lung, breast, and most recently kidney; a brain cancer indication is expected in late 2009. GlaxoSmithKline’s pazopanib, an oral VEGF agent close to being approved, is effective against advanced kidney cancer. 

Kinases and VEGF are popular targets for cancer drug development because every tumor depends on pathways associated with them. Less popular approaches include agents that induce or prevent apoptosis (programmed cell death), cell cyle, enzyme inhibition, immune stimulation/suppression, and receptor binding. 

Some worry that kinase and VEGF agent classes are already suffering from over-crowding. When Phase III data on pazopanib were presented at an American Society of Clinical Oncology meeting in June, Primo Lara, MD, from the University of California, Davis, called pazopanib a “me-too” drug for its similarity to agents already on the market. Newer drugs, he argued, should work better, cause fewer side effects, or cost less. “Pazopanib has not met any of these criteria,” Lara said. 

The danger of not approving what appear to be copycat cancer treatments is the possibility of losing a drug that might work wonders in the right patient group or in a different cancer. Phase III data for Genentech’s breast cancer drug, Herceptin (traztuzumab) were uninspiring because the study failed to focus on patients who over-expressed the Her2neu biomarker. Once that criterion was applied, Herceptin became a blockbuster. 

Similarly the monoclonal antibody ipilimumab (BMS/Medarex), which works by stimulating the immune system, was originally tested in melanoma patients but early clinical results were mixed. In one study released in 2007 the drug was no more effective than placebo in treating advanced skin cancer. But in June 2009, the Mayo Clinic announced that two men with advanced, aggressive prostate cancer were cured by the drug. 

Antibodies remain an active area of R&D for oncology despite falling short of “magic bullet” status early developers had hoped for. Today, most cancer antibodies (and other biologics) are administered by injection or infusion, alongside conventional chemotherapy. Antibodies target tumors by killing cancer cells that carry specific protein markers. Thanks to the high specificity of today’s antibodies, there has been renewed interest in antibody drugs that carry a toxic “payload” directly to cancer cells. Antibodies are considered targeted therapies but, like chemotherapy drugs, they operate on cancer cells rather than underlying biological pathways. 

Notable cancer antibodies include Genetech’s Rituxan (rituximab; for treating non-Hodgkin’s lymphoma) and Herceptin, and Erbitux (cetuximab; BMS/Merck/Imclone) for pancreatic and lung cancers. Two cancer antibodies, ipilimumab (BMS/Medarex; melanoma, prostate cancer), and Arzerra (GSK’s and Genmab’s ofatumumab, for lymphoma and leukemia), are in late-stage testing. 

	The advent of cancer pills that patients take at home is revolutionizing the oncology marketplace on several levels. Just 10% of marketed oncology medicines are taken orally, but this segment is expected to comprise 25% of treatments within five years. Oral, targeted cancer drugs tend to be more effective and far less toxic than old-line chemotherapies, but greater effectiveness comes at a price. 

For example, BristolMyers Squibb’s Sprycel (dasatinib) leukemia drug costs close to $4,000 for a month’s supply, and Pfizer’s Sutent kidney cancer medicine costs $5000 for 28 pills. It is not unusual for drug plans to impose significant copays—20% to 30%&mdash;for these treatments, or refuse to cover them when they are used off-label. 

Oral treatments cut into oncology practice profitability as well. Until fairly recently, oncologists acted as de facto pharmacists, stockpiling chemo drugs and re-selling them for whatever price insurers would pay. This practice, known as “buy and bill,” accounted for 30-50% of oncologists’ income. The only good thing one could say about the practice is that chemo was generally covered 100% as a medical treatment, whereas patients pay significant sums, sometimes 100%, for cancer pills. In 2005 Medicare limited the mark-up to 6% and private plans quickly followed suit. Oncologists complain that 6% barely covers costs associated with purchasing, inventorying, and tracking intravenous drugs, although they may still charge the going rate for dispensing them. 

Cancer treatment decisions are optimally based on clinical factors. But to remain profitable in today’s economic environment oncologists must familiarize themselves with such terms as working capital, human resource costs, practice efficiency, and opportunity costs, observes Susan Dennis, an internal oncology expert with healthcare analytics firm SDI (Plymouth Meeting, PA). In some instances medical decisions may be based on what insurers pay doctors for conventional chemo administered in a clinic, and what they will reimburse patients for pills taken at home. “The typical community oncologist must re-evaluate every facet of their practice to recoup the revenue loss incurred with reimbursement changes,” Dennis says. 

Since doctors make no money on medicines patients obtain from a pharmacy, cancer pills will cause oncologists’ incomes to deteriorate even further. One need not be too cynical to detect the potential for conflict of interest, as doctors have a financial disincentive to prescribe what may be a more effective medicine. In fact oncologists are keenly aware of the economics. A January 2007 study in the Journal of Clinical Oncology reported that 42% of oncologists regularly raised drug-cost issues with patients, 23% said cost affects treatment decisions, and 16% don’t mention very expensive drugs to patients they think cannot afford them. 

Advocacy groups, including the American Cancer Society, are lobbying states to mandate equivalent reimbursement for oral and infused cancer drugs. Twenty-five states are considering such laws but only Oregon has one on the books. Equivalent reimbursement, while appealing to our sense of fairness and compassion, will raise healthcare premiums and likely exacerbate the perverse incentives for oncologists to prescribe less-effective drugs. 

“The economics of oncology therapy are just goofy,” observes Clarient’s Kenneth Bloom. Oncology drug prescribing needs gatekeepers, Bloom argues, and pathologists—physicians who examine cancer tissue from biopsies and surgeries&mdash;are in the best position to serve in that capacity. By examining cells microscopically and testing them for various attributes, they have a better grasp on the biology of cancer than do medical oncologists, who prescribe based on a tumor’s organ of origin. Biology- or pathway-based prescribing will be essential for optimal utilization of the emerging classes of oral cancer drugs. “The key is breaking out beyond organ classification for cancer, to a molecular definition,” says Richard Wagner, PhD, senior director at MattsonJack (Foster City, CA), an industry consulting firm. 

Bloom is also critical of how cancer drugs are tested against organ-based diagnoses instead of cancer pathways. That, he says, is one reason why half of all cancer drugs end up being used off-label, a practice he believes serves neither patients nor the healthcare system at large. No scientific evidence exists, for example, for 70% of off-label chemotherapy use in breast cancer, according to a study presented at the recently held ASCO meeting. 

An article in the May issue of Managed Care quoted John Frick, director of pharmacy at Blue Cross & Blue Shield Assn. (Chicago), on off-label use of cancer drugs: “Instead of saying ‘It couldn’t hurt,’ we should be asking ‘How will this help?’ That is the real question.”

	Off-label use is rampant in cancer therapy, but one can understand that physicians and patients feel obligated to “do something,” even when science suggests otherwise. Less comprehensible is poor compliance to drug regimens, which appears to be as prevalent in cancer as in other diseases. Cancer patients, fearing side effects, often fail to show up for chemotherapy sessions. Cancer pills, notes Paul Boni, chief research officer at Grail Research (Cambridge, MA) are easier to quantify despite the well-known adherence gap for self-administered medications. 

Manufacturers claim that adherence to newer cancer treatment is good, but research indicates this may be wishful thinking. Adherence to drug regimens depends to a large extent on the patient’s perception of their disease. A 1987 study found compliance to oral medication regimens in newly-diagnosed leukemia patients to be “remarkably low” at the stage when patients might not feel sick. Little has changed in two decades, as adherence for self-administered drugs still hovers at around 50% six months after the initial prescription is filled. While adherence is high for patients in supervised settings, or during the acute stage of disease, manufacturers worry that pills will go untaken as indications are broadened. Patients are less likely to stick to their treatment in situations where dosing is unsupervised, the objective is to prevent recurrence, patients do not perceive an immediate benefit, or they are taking several other medications. “Patients are trying to process lots of things patients at the same time,” observes Joanna Schwartz, PharmD, an oncology pharmacist and professor of pharmacy practice at the Albany College of Pharmacy (Colchester, VT). 

Of all the factors affecting compliance, drug costs are perhaps the most intractable. With oral cancer drugs priced at $2,000 to $8,000 per month, patients skip doses or fail to fill prescriptions altogether. A report in the journal Blood earlier this year estimated that one-third of patients taking Gleevec for leukemia were non-adherent, and just 14% of patients fully complied with their drug regimen. Gleevec costs $3,600 per month. The numbers are astounding when you consider that this drug is a model of effectiveness for a once-fatal illness: Gleevec has kept some patients alive for ten years. 

	Paul Boni refers to oncology as a “privileged market” because of cancer’s seriousness, and the relative dearth of truly effective medicines. “There hasn’t been much push-back or resistance from payers,” a fact that has caused cancer drug sales to rise faster other medicines’. 

Nevertheless, companies realize that no matter how well their products work they cannot expect unlimited reimbursement. Many of the most expensive cancer drugs now carry per-patient cost caps, which provide patients with as many doses as they need but limit how much insurers pay. 

Pricing pressures are originating from the payer side as well, particularly with respect to “specialty pharma”—drugs that require special handling before administration. “It used to be off the radar screen; payers had other things to worry about. But now it’s hitting the breaking point,” Boni says. Payers are hitting back not with traditional tiering, but with requirements for prior authorizations and larger copays, which grow even more with off-label usage. 

Oral cancer drugs are expensive, “but so are many other aspects of cancer care including diagnostic radiology and lab, surgeries, and radiation therapies,” observes Lee Blansett, SVP at MattsonJack. And diabetes, that poster-child of chronic illnesses, reportedly costs the U.S. healthcare system $191 billion per year, a figure that continues to rise. Exorbitant costs have been explained by the relatively small patient populations for which the drugs are approved, high late-stage clinical trial failure rates, and high development costs. The economics are actually quite simple: development costs are roughly the same whether the drug is indicated for 20 million people or 20,000. Perhaps the most charitable thing that can be said of high-priced cancer drugs is that patients do not survive long enough to bankrupt pharmacy benefit plans. “Very few cancer patients get to spend $80,000 on any one drug in one year,” Blansett notes. 

One could argue that the price differential for cancer pills shrinks when total utilization costs and value are factored in. The point of targeted therapies, after all, is that only susceptible patients receive them, and insurers need only reimburse when the medicines are used appropriately. 

On the value side, some oral cancer drugs have been shown to double or triple survival time compared with less expensive chemotherapy. Novartis’s Gleevec, which works in about 90% of cases of chronic myeloid leukemia, has transformed this once-deadly cancer into a manageable disease. A National Bureau of Economic Research working paper, authored by Cornell researchers and released in July,* calculated that the value-adjusted cost of colorectal cancer drugs was 30% lower than a decade ago if longevity and quality of life are factored in. The study examined data on a combination regimen of Genentech’s Avastin with two chemo drugs, compared with a single chemotherapy agent that was the standard of care in the mid-1990s. It concluded, based on actual prices and effectiveness, that Avastin’s $36,000 cost for 24 weeks of treatment was “lower” than that of the single chemo drug. 

This line of reasoning works now perhaps, when the number of targeted therapies is small and most add just a few extra weeks or months to patients’ lives. The Cornell researchers will need to dust off their calculators as more such drugs are approved, and second- and third-generation therapies routinely extend life by years or decades for broad swathes of cancer patients. PC 

*A Quality-Adjusted Price Index for Colorectal Cancer Drugs,” by Claudio Lucarelli and Sean Nicholson, Cornell Univ. Dept. of Policy Analysis & Management; NBER Working Paper No. w15174, available at

Oncology drug development pipelines are overflowing, but the sky-high prices of these agents are turning reimbursement schemes, and the very practice of cancer medicine, on their heads

Oncology Drugs Add Promise, Stresses to Healthcare Delivery

	Do you know what your cancer drug is up to? Answering that question is not as simple as for medicines taken by well-defined patient groups, or principally for one disease. Yet among drug classes oncology treatments hold a unique position: A frightening disease of immense scientific interest, hundreds of pipeline drugs and nearly as many protocols for single and combination treatments, a complex distribution and reimbursement, and—as information service companies tell us&mdash;unprecedented opportunities for those with the right data.

Kalorama Information estimates the worldwide cancer drug market at $54 billion. Oncology’s share of global pharmaceutical demand, while only about 5% in dollar terms, is growing at more than 10% per year. 

Much of oncology practice is guideline- or protocol-driven, but a good deal is based on cancer doctors’ experience, journal reports, and information from conferences. Off-label prescribing, which is relatively rare for some conditions, is quite common in cancer therapy. 

Drug utilization data have long provided critical feedback for pharmaceutical marketing, product lifecycle management, and development of best clinical practices. Oncology drugs take the information game to a new level because cancer and its treatment are qualitatively and quantitatively different from other diseases. Knowing how many pills were sold in what area or prescribed by what medical specialty is not enough. Drug firms demand much more, and information providers have so far delivered detailed data to suit every need. 

Oncology data come in a wide variety of types, including complied prescriber data, clinical practice data and processed claims. Providers range from add-on business services offered by wholesalers (McKesson’s Specialty Care division, and AmerisourceBergen Specialty Group), to the market-data services of IMS Health (Conshohocken, PA), SDI Health (Plymouth Meeting, PA), IntrinsiQ LLC (Waltham, MA), to oncology practice management firms like Synovate Healthcare (Lawrenceville, NJ), Accelerated Community Oncology Research Network (Memphis, TN) or IMPAC Medical Systems (Sunnyvale, CA), to business consulting firms like Mattson Jack Group (St. Louis). There are also patient registries and practice guidelines compiled at the American Society of Clinical Oncology and NIH. 

A customer of IntrinsiQ’s notes, “I don’t think any one data source or vendor supplies an all-encompassing perfect set of data. There are strengths and limitations to each.” Moreover the robustness and freshness of the data are significant factors (some datasets can lag current practice by as much as six months), as well as the nature of the business questions for which answers are being sought. “Any vendors who continue to add depth and breadth to their data tend to be well regarded,” he says, noting that Intrinsiq started out providing software to physicians to help them avoid overdosing their patients with IV chemotherapeutics.” Now, “IntrinsiQ can capture the entire regimen the patient receives, including oral chemotherapies, how much and how frequently the patient receives each drug and for how long, diagnostic tests performed on that patient, how these tests influence treatment decisions, and what supportive care that patient received.” 

	Information-selling has become a natural side business for pharmaceutical distributors who are ideally positioned to parlay utilization data into marketing knowledge. Onmark (South San Francisco, CA), a group purchasing organization within McKesson Specialty Care Solutions, boasts 3,000 member clinics and 4,800 physicians who benefit from Onmark’s relationships with 18 manufacturers of about 100 oncology drugs. McKesson Specialty also distributes drugs for rheumatology, urology, ophthalmology, dermatology, and is investigating nephrology. 

McKesson’s and Onmark’s information products include practice-level software, Lynx, and the IQ service for drug companies. Lynx, adopted by 1,500 oncology practices with an additional 250-300 installed in hospitals, streamlines charge capture, inventory management, dispensing, reporting, ordering and billing. More than 2,800 physicians use Lynx for approximately 50 cancer diagnoses. 

Practices pay a nominal fee for Lynx if they agree to share data with McKesson, which massages the information and sells it to drug manufacturers through a service called Integrated Quality (IQ). IQ became possible as a result of the 1.3 million unique patient-treatment incidents captured by Lynx since 2000 (with additional records accumulating at a rate of 290,000/yr). Administered by Onmark, IQ provides insight on how oncologists use drugs individually and in combination. A physician feedback component helps to reinforce practice guidelines for “appropriate use.” 

Onmark’s first IQ program, on treatment for white blood-cell depletion resulting from chemotherapy, was released in May. It found that just 65% of doctors prescribed a white cell booster in elderly patients treated for non-Hodgkins lymphoma while guidelines call for every patient to receive the drug. “Manufacturers of these agents view this information as an opportunity for 50% sales growth,” says Mike Cunningham, PharmD, VP and GM at McKesson Specialty Care Solutions. 

Because IQ is an opt-in program, it is possible to re-survey oncologists to determine why they did not prescribe a treatment. This dialog informs physicians about treatment guidelines and provides them with comparisons between their practice and others.

Physicians benefit from compliance “because there are a lot of pay-for-quality initiatives afoot,” Cunningham observes. “More importantly, they can evaluate how well they’re doing from a quality perspective.” Drug companies, in turn, learn in near real time of any unfavorable clinical or reimbursement experiences with their products. “The worst thing that can happen is the provider has a negative experience and may not be willing to use a particular product in the future.” 

IntrinsiQ (Waltham, MA) is another company that collects fees from information providers and pharmaceutical industry clients. Oncologists pay to use use Intellidose, IntrinsiQ’s oncology medical management system, while drug companies purchase the information Intellidose generates. 

Oncologists use Intellidose track office-administered drugs from the time they enter the practice to when patients receive them. The software controls inventory, stores patient information, performs and double-checks dosing, archives notes related to care, provides charge capture for billing, and can even trigger ordering of medicines. Oncologists have long profited from purchasing and administering cancer drugs, but without inventory and reimbursement management the cost of high-priced medicines can overwhelm a practice. 

IntrinsiQ’s customers include twenty-eight of the world’s thirty top pharmaceutical companies, according to Julie Maloney, director of client services, plus smaller firms. Each information package is tailored to the customer’s needs because “not every company looks at the market the same way,” Moloney says. “They’re not only looking at their own drug, but those of competitors.” That, says Moloney, distinguishes IntrinsiQ’s data sets from raw sales printouts. “We can tell them when, where, and how a drug is being used, on what kind of tumor, what stage of the disease, in which line of therapy, and how much drug was administered to individual patients.” 

Intellidose tracks the drug prescribing and administration habits of more than 600 physicians across the United States, and logs two million drug administrations per year. The system also notes usage of ancillary treatments that mitigate the side effects from cancer drugs, such as nausea, lack of appetite, and blood cell depletion. Back-end software tracks drug use over time in patients sorted by demographics, cancer type, stage of disease, and course of treatment. Once the information enters the system it is anonymized, aggregated, projected to the national level, and delivered to clients. 

Steve Gavel, Global Marketing Director for Oncology at IMS Health (Plymouth Meeting, PA), agrees that data alone provide a rather narrow view of the oncology marketplace. For this reason IMS clients who purchase the company’s data and require greater depth and interpretation also subscribe to IMS consulting services as an add-on feature. “Clients frequently have questions whose answers cannot be found in DDD alone,” Gavel says. He is referring to DDD Integrated Views, a database linking healthcare system purchasing dynamics with sales dollar volumes. “Many of our clients require supplementary consulting and primary market research to accompany their quantitative research.” Additional IMS product offerings, such as Oncology Analyzer, are often used with DDD and other quantitative tools to provide further insight. 

	Not every information services company obtains its data from cold, hard sales figures. With the right incentives it is possible to get oncologists to take time from their busy practices to tell research firms what they think. 

NMCR Analytics’ (Frisco, TX) flagship product, Challenging Cases, captures live market research data from physicians recruited from parent company AmerisourceBergen’s network of self-registered oncologists. Doctors receive “fair market” non-cash compensation for participating anonymously in the nearly day-long exercises. Challenging Cases mimics the “tumor board” case-based format in which oncologists review patients and treatment options as they would in clinical practice. 

Pharmaceutical company clients receive a demographic breakdown of participants and response statistics grouped by participant’s sex, type and size of practice, group purchasing organization affiliation, region of the country, and years post-training. Participants, who are similarly blinded to clients, are recruited from AmerisourceBergen Specialty Group’s network of self-registered oncologists. 

As the Challenging Cases session continues the case morphs through a series of deliberate alterations. Questioning leads participants through a maze of variations on the now-hypothetical patient’s age, sex, ethnicity, treatment success or failure, relapses, economic and insurance status, other illnesses, daily living status, and other relevant factors. 

Questions are designed by NMCR’s in-house clinical staff with or without drug company input. From the responses NMCR generates client-specific data or original research which it may publish on its own. 

“Manufacturers are looking for nuances in market segmentation to gain a better understanding of how their products are utilized, in what patient types, and what trigger factors are important to treatment options,” says Kristine Lemke, group VP of NMCR Analytics. 

Lemke acknowledges that traditional market surveillance and sales data have their place but are limited in value. “They tell you what the medical oncologist did. We get closer to the decision process by challenging the doctor to describe what he or she would do. Knowing what goes on in the hearts and minds of these doctors, when faced with certain patient types, is very valuable.” This approach also measures doctors’ uptake of drug company messages, for example if community doctors are aware of the latest data, whether they know how to utilize it, and if they have ever followed its recommendations.

	While NMCR’s data are not specifically designed for formulating treatment guidelines and protocols, they have been used in dossiers to support reimbursement as well as changes in evidence-based oncology guidelines. “I can’t tell you the percentage of the time this happens but I know it’s been done,” Ms. Lemke told 

Lemke claims that Challenging Cases can predict prescribing patterns well before sales data confirm them. NMCR presented a poster at the 2008 ASCO meeting that showed a three-year analysis of the expected use of a particular cancer-drug combination in prostate cancer. This data captured “early intent to treat” market trends by medical oncologists before post-surveillance market information. The manufacturer’s actual sales data correlated nearly perfectly with NMCR’s prediction. 

TargetRx also takes the prospective physician survey approach, but with a more traditional doctor-focused marketing angle. The company analyzes survey data to predict future prescribing and to inform drug firms on how they might change the anticipated outcome. 

TargetRx describes the four forces that drive physician prescribing as the product, patient, payer, and promotion. “By capturing information from physicians on each of these forces, we tell pharmaceutical companies what’s happening, what the doctors think, where they learned it, and how that affects the likelihood they will prescribe a particular product,” explains Michael Luby, co-founder. 

Unlike MNCR, TargetRx pays a cash honorarium to participating doctors. But that is apparently not what makes oncologists sign up because, as Luby notes, “a lot of people are throwing money at doctors.” Oncologists, he says, value that drug companies seek their opinions, that their ideas may affect how drugs are marketed to them, and that TargetRx surveys help them keep abreast of new therapies. 

TargetRx does not release income figures but Luby says the firm’s oncology business has increased five-fold since last year. “Demand has been intense.” Several thousand oncologists have registered with the firm to participate in surveys. 

Some of the most useful information from TargetRx surveys pertains to drugs within a year of launch. By then, oncologists will probably have heard of such products through journals, meetings, or education programs. Doctors’ opinions at this point, says Luby, are uncannily predictive for how the drug will be utilized within its first few years on the market. “It’s amazing how telling those signals are, even when your questions are open-ended and you don’t give the doctors a lot of data.” By six months pre-launch many oncologists will have already decided how to use the drug and in what combinations. Sponsors can use this information to design educational programs around the launch and beyond. This, says Luby, is when companies can decide whether to pursue the product’s natural positioning or to try a non-traditional approach. 

The industry appetite for data—both business and clinical&mdash;is bottomless. When asked about the “ideal” information service, the Intrinsiq client noted above had this list&mdash;as a starting point: 

Patient demographics: Age, gender, race (some cancers/subtypes of cancer are more prevalent in specific races). 

Physician demographics: practice size, type, and location, physician specialty, number of years in practice. 

Patient characteristics and treatment: Agents/regimens the patient received, dosing regimen, duration of treatment, by stage and line, concomitant treatments (hormones, anti-emetics, supportive care, other treatments the patient is receiving (some cancer drugs are contra-indicated if the patient is already receiving other non-oncology products), diagnostic tests performed, surgical history for the cancer, radiation treatment history. 

Reimbursement details: Payor and copay levels, claims, denials, reasons for denial. 

Promotional information: Number of rep details, detail minutes; physician recall of rep message, physician impression of product, any impact on drug prescribing patterns as a result of rep visit.

But he notes that “of course, this resource would be prohibitively expensive!” and says that “the challenge for the pharma industry is to compile all this information, to build a landscape that most accurately reflects true physician attitudes, practices and patient treatments.” PC 

BOX: QUANTIFYING THE PRESCRIBER-PATIENT DIALOGUE

	There seems to be no limit to where data-miners will go to get their information. Verilogue (Horsham, PA) records and archives in-office conversations between oncologists and patients, capturing information “across the journey of care” according to CEO Jeff Kozloff. The goal is to provide drug companyies with better understanding of how oncologists and patients interact at different stages of disease and treatment. 

Verilogue takes the audio files, from conversations lasting between two minutes and two hours, and transforms them through computer algorithms and linguistic analysis into data useful for crafting educational and marketing messages that improve caregiver-patient communication. Through one study, for example, Verilogue determined that physicians use language associated with war or athletic competition while patients prefer softer terms connoting faith, trust, and personal journey. Conclusion: Doctors need to show better interpersonal skills and adopt language that transmits feelings of confidence and trust. 

Other goals include putting oncologists and patients on an equal footing in the examination room, uncovering communication gaps, and determining what language works and what does not. “There’s been a big focus by drug companies on relationship management and relationship marketing, how to support these to improve treatment outcomes,” Kozloff says. 

Sharpening doctors’ psychosocial aptitude is not the only use for this information. Companies are eager to learn what drives the treatment continuum, for example the decision to move to a second-line therapy. Verilogue claims its product can help companies achieve that. 

A fast-growing market supports more, and more comprehensive, data services

Tracking the Evolution of Oncology Drug Prescribing

	Historians often cite the early 1980s as the dawn of biotechnology but in fact vaccines — arguably medicine’s greatest achievements – existed two hundred years earlier. Vaccines may be undergoing a “golden age,” according to Rino Rappuoli, PhD, who heads research at Novartis Vaccines’ Siena, Italy facility, but they have not always been an exciting business. Liability issues and low margins led to brutal consolidation, which reduced the ranks of vaccine-makers licensed in the United States from twenty-six in 1967 to twelve in 2002. The fallout from manufacturer attrition is still felt as just five companies – Merck, GlaxoSmithKline, Sanofi Pasteur, Wyeth, and Novartis – control 97% of the market.

The current buzz about vaccines arose from the success of blockbuster products like Merck’s Gardasil (introduced in 2006) and Wyeth’s Prevnar (2000). Another boost occurred after the 2001 terrorist attacks, when concerns over bioterrorism prompted the federal government to fund expansion of vaccine production capacity. More recently interest in vaccines for malaria and other diseases endemic to developing countries has attracted funding from the Bill and Melinda Gates Foundation and other philanthropies. And all along advances in biotechnology, particularly in genetics and cell culture, have unlocked vaccine targets and production methods that did not exist a decade ago. 

	Kalorama Information (New York) estimates global 2009 vaccine revenues at $22 billion, split approximately evenly between pediatric and adult products. The vaccines business is growing at between 12% and 15% per year. Top pediatric vaccines leading market growth are Wyeth’s pneumococcal vaccine Prevnar, and Merck’s RotaTeq vaccine for rotavirus. Leading adult vaccines included Gardasil, for sexually transmitted human papillomavirus (HPV), and Zostavax, for shingles, both from Merck. To put these figures into perspective, pharmaceutical sales were approximately $550 billion and the three top-selling drugs alone — Lipitor (and generics), Advair, and Plavix – enjoyed combined sales of $26 billion in 2006. The double-digit growth rate of vaccine products, though, puts them in an attractive opportunity path. 

While influenza vaccines are and probably always will be volume leaders, they accounted for just $2.8 billion in revenues in 2007, according to Kalorama, and sales are divided among six manufacturers: GSK, ID Biomedical, CSL Biotherapies, MedImmune, Novartis Vaccines (formerly Chiron), and Sanofi. Kalorama expects 14% growth in this market segment through 2013. 

In its analysis Kalorama notes the “Gardasil effect,” referring to the phenomenal rise of Merck’s Gardasil vaccine against HPV, a family of viruses that cause cervical cancer. Gardasil’s 2006 debut is partly responsible for this decade’s resurgence of vaccine revenues. Sales of the vaccine quickly reached $1 billion but have recently flattened.

	Yet opportunities for considerable growth still exist in this market. Gardasil protects against four of the most common (out of several dozen) strains of HPV. Merck is planning an improved version that confers immunity against nine strains. A competitor, GSK’s Ceravix (approved in Europe but not the US), guards against two strains but claims more robust protection. Both products, and future HPV vaccines, could also be approved for young men, the principal vectors for HPV transmission, which would essentially double demand. 

The Gardasil effect reaches well beyond HPV, which some have described as a niche market. Of the eight most significant cancer-causing microorganisms, vaccines exist for just two (HPV and hepatitis B). Helicobacter pylori, a bacterium that infects half the world’s population, causes gastric cancers and 95% of all stomach ulcers. A vaccine against this agent would be an instant blockbuster, as would immunizations against most of the microorganisms listed in Table 1. All cause mild to serious primary infections and, years later, deadly cancers. 

	Not everyone subscribes to the Gardasil model or the idea that vaccines are undergoing profound scientific and economic transformations. Alex Kanarek, PhD, senior consultant at BioProcess Technology Consultants (Acton, MA) believes that commodity pricing for at least half of all administered vaccines will swamp out blockbuster effects. “Half of this business is high-volume low-markup,” he observes. 

Panic over pandemic influenza is another factor which has been partly responsible for the renewed excitement in vaccines, but Kanarek calls this a “distortion” of the marketplace rather than a permanent trend. During the mid-2000s the U.S. and other governments paid vaccine-makers to ramp up manufacturing capacities, which gave a false impression of prosperity. None of these facilities, Kanarek says, would have been ready had a pandemic actually hit. Our unpreparedness for the current swine flu outbreaks supports Kanarek’s contention. 

Nevertheless, Kanarek admits that Gardasil could become a model for future vaccine development which, at least on a value level, could be dominated by high-priced, relatively low-volume products. 

Another problem with the Gardasil model is that governments, the principal payers in most developed countries, will likely reject expensive vaccines with undemonstrated efficacy, particularly for diseases that might be viewed as avoidable. Gardasil costs about $350 for the recommended course of three injections but the immunity it confers is of uncertain duration, and determining the extent to which it prevents cervical cancer will take years.

	A vaccine’s effectiveness depends, in large part, on “herd immunity,” a term that refers to the percentage of the transmitting population that is vaccinated. Where full vaccination compliance covers a multitude of shortcomings by reducing exposure, spotty vaccination magnifies them. In other words, vaccines like Gardasil lose cost-effectiveness when coverage is less than complete. 

“Even for inexpensive vaccines, convincing prescribers and consumers that it’s in their best interests to be vaccinated is becoming difficult,” notes Claude Allary, president of consulting firm Bionest Partners (Paris). The value proposition is further clouded, Allary says, when individuals pay their own way. “I don’t think we’ll see too many more of these types of vaccines succeeding for avoidable risks. They are great scientific achievements but I’m not so sure that in the coming years government payers will accept these products.” 

	Pandemic influenza, bioterrorism, and emerging infectious diseases have raised the ante for vaccine-makers and created a “more commercially interesting” environment as well, notes Nigel Darby, PhD, GM for biotechnology at GE Healthcare (Uppsala, Sweden). So have technologies like virus-like particles, DNA vaccines, therapeutic cancer vaccines, and novel delivery methods. Consequently, vaccine development pipelines are as healthy as they ever were: Approximately 300 new vaccines are in various stages of development.

	But if you thought drugs suffered long, convoluted development timelines, pity the vaccine developer. 

Vaccine clinical trials tend to be large, and establishing a clinically relevant endpoint is nowhere nearly as straightforward as with pharmaceuticals. “With drugs, you’re trying to balance effectiveness and safety with the risk associated with the disease,” observes George Kemble, PhD, GM for vaccines at Medimmune (Gaithersburg, MD). Late-stage drug study subjects are already sick, while vaccine trial participants are healthy and may not, for obvious reasons, be challenged with the infectious agent under study. “This imposes a much higher safety burden than for drugs, and adds a huge amount of time to vaccine development.” As a consequence, most vaccines carry FDA-mandated postmarketing surveillance requirements. 

As with drugs, vaccines undergo three-phase clinical testing before FDA considers them for approval. Unlike pharmaceuticals, where efficacy endpoints are generally straightforward and quantifiable (Does the patient’s condition improve? Is her cholesterol lowered?), a vaccine’s effectiveness is harder to demonstrate as it involves dealing in negatives (The subject did not contract polio — so what?). Studies have only rarely included a pathogen challenge to healthy human subjects. Sponsors must therefore rely on surrogate indicators of immunity such as generation of antibodies whose protection may be incomplete or not a function of their concentration in the blood. The other common endpoint, protection from infection, takes many patient-years to establish statistically. 

FDA’s “two-animal rule,” promulgated in 2002, provides an alternative route for establishing Phase III-worthy efficacy. The rule permits sponsors to petition for approval after safety and dose-ranging (Phases I and II) studies based on a vaccine’s effectiveness in two animal models. The rule is applied only for diseases that human subjects are not likely to encounter such as anthrax and plague. In any event testing is “complex, difficult, expensive, heavily regulated, and unique for each vaccine,” according to Rangappa Ramachandra, PhD, of Covance Immunology Services (Denver, PA). 

What about seasonal flu vaccine, whose composition changes annually without sufficient time for human testing? No drug analogy exists for such vaccines, even among generics. The secret lies in regulatory-legal custom which dictates that for biologicals the “process is the product.” Manufacturers are thereby permitted to swap virus strains into and out of their vaccines provided their manufacturing process remains identical. 

The manufacture of medicines has a well-deserved reputation for fustiness, which carries through to vaccines as well. Consider that the egg-based method for producing influenza vaccine has chugged away for sixty years with only modest tweaks. Such legacy processes persist because they work, and profit margins do not justify changing them. But they lack the versatility and flexibility that the current healthcare and investment environments demand. 

Vaccines are clearly a case where the basic science “is developing much faster than the manufacturing technology,” according to Dr. Darby. “Pandemic influenza preparedness, for example, will require up to three billion doses of vaccine, which is five times the world capacity.” Threats of bioterrorism and emerging diseases like SARS create a related need, for flexibility. 

Working through a grant to develop rapid manufacturing for pandemic influenza vaccine, Novavax (Rockville, MD) saw an opportunity to promote virus-like particles, a novel production platform that eliminates the use of infectious agents in vaccines altogether. Merck’s blockbuster vaccine Gardasil employs virus-like particles. Novavax teamed with GE Healthcare on a fully disposable process that provides up to ten times the yield, per production volume, as either cell culture or the more common egg-based flu vaccine manufacture. GE and several other vendors have begun to investigate a vaccine “factory in a box,” based on cell culture technology, that can be more or less drop-shipped to a region in need of such a facility. 

Novavax claims a 1000-liter process, housed in a $6-million facility, could produce one million doses of patient-ready vaccine per week, just three months after identifying the pandemic strain. The egg method takes twice as long, at a capital cost of between $200 million and $400 million. Flexible, low-cost facilities would be invaluable during a pandemic since they can be constructed almost anywhere and distribute vaccine locally. Novavax shares rose as much as 360% during the first few days after the swine flu outbreak was announced, but have since fallen by half. 

Value-added activities not uniformly successful

	Novel vaccine delivery, “adjuvanting,” and combining two or more antigens in a single product are recognized strategies for enhancing a vaccine’s medical and economic value, but results have been mixed. 

Compliance and single administration are factors behind the success of combination vaccines like the DPT (diphtheria-pertussis-tetanus) vaccines that have been available for many years. Sanofi-Pasteur’s Pentacel pediatric vaccine, approved in 2008 in the United States, protects against five agents: DPT plus polio and Haemophilus influenza type b.

	Vaccine delivery has provided some interesting benefits as well. MedImmune’s FluMist intranasal influenza vaccine quells patients’ fears of injections and serendipitously reduces the incidence of flu from about 10% to 5% in children, compared with injected vaccine. George Kemble, PhD, GM for vaccines for Medimmune, attributes this benefit to the unique activity of live, attenuated viruses in flu-naïve patients. 

Medimmune, since 2007 the biologics unit of AstraZeneca, has worked hard to improve Flumist. The only flu vaccine not administered by injection, Flumist was approximately thirty years in development, two-thirds of that time in an academic setting. Last year Medimmune obtained approval for a “high temperature” version which can be stored in a refrigerator (vs. a freezer), which greatly reduces storage and handling burdens.

Yet FluMist has failed to penetrate the market to the degree it should have. Similarly patches, microneedles, pulmonary delivery, and needle-free injection are exciting developments but none have gained significant traction. To succeed, developers will need to demonstrate unique benefits (compared with injection) that overcome prescriber resistance and suspicions, even from needle-wary consumers. 

Adjuvants — immune-stimulating substances added to vaccine formulations or chemically attached to the antigen, are another strategy for adding value to vaccines. Despite the fact that alum – a simple compound of aluminum – is the only adjuvant approved in the United States, adjuvants continue to enthrall vaccine developers. Dr. Rappuoli of Novartis claims his company has an adjuvant in development which, when combined with a vaccine against “H1” influenza, will confer permanent immunity to all similar strains of flu. H1 strains predominated in 2003 and 2004. Both the 1918 global pandemic strain, and the swine flu outbreak of 2009 involve H1-type virus. As exciting as this adjuvant may appear in laboratory studies U.S. regulators examine immune stimulants very closely. 

A work-around to improve immune-stimulation without inventing or adding anything to the vaccine cocktail is to make the antigens themselves more immunogenic. Companies like GlycoVaxyn (Geneva, Switzerland) build in immunostimulation by inducing bacteria to incorporate specific types of sugars on their antigens. This strategy is unlikely to reassure regulators, however, since the wrong type of glycosylation, as the sugar-adding process is called, can cause severe immune responses and represents a major controversy in establishing a legal-regulatory framework for biosimilars (biological “generics”). 

	Despite technologic and regulatory hurdles vaccines will remain at the cutting edge of medicine for many years. Vaccines stand out as arguably the greatest benefactors of breakthroughs in genetics and protein research that have revolutionized biology, a fact not unnoticed by drug companies. “All of big pharma want to be in vaccines,” notes Rino Rappuoli of Novartis. 

Yet with pharmaceutical sales dwarfing those of vaccines it is easy to overlook the adage about “an ounce of prevention” which is, after all, what vaccines provide. “Vaccines have become a growth area because patients and payers see prevention as more cost-effective than treatment,” observes Michel DeWilde, PhD, SVP for R&D at Sanofi Pasteur (Swiftwater, PA). Dr. DeWilde cited the emergence of antibiotic-resistant bacteria, which cause tends of thousands of deaths per year in the United States. “However, the difficulty of the targets that remain in vaccines is underestimated. The low hanging fruit is gone.” PC 

	Although the current number of actual vaccine manufacturers in the United States is small, the recent acceleration of R&D efforts for new vaccines suggests that in the coming decade we may witness the launch not only of new companies, but of many new vaccines. Whether these new products will succumb to the same market, regulatory, and public-sector forces that heretofore have contributed to the pattern of

	dominance in many fragile vaccine markets, eventually resulting in only or two suppliers, or whether we have now finally reached and gone beyond a turning point, remains to be seen.

— From “U.S. Markets for Vaccines,” E.R. Berendt, R.N. Denoncourt, A.C. Warner,

	published by AEI Press, Washington, DC, 2009.

Spurred by some recent successful launches, and with hefty R&D funding commitments, the vaccine business is booming