Does the European Union need a drug safety watchdog separate from the authorities who approve drugs for marketing? The head of the European Agency for the Evaluation of Medicinal Products (EMEA) says yes, and his statements have pharma companies worried about potential development delays. 

In the absence of a centralized procedure, EMEA currently relies on authorities in the 25 member states to collect and collate drug safety data. But in the wake of the recent withdrawal of Merck's Vioxx (rofecoxib), director general Thomas LÃ¶nngren has called for a better method, telling the 

that there is an urgent need to build up independent networks of intensive drug monitoring.  

EMEA's authority and power are not as wide as FDA's. Most medicines now have to go through the agency for union-wide approval, but in many areas EMEA functions mostly as a coordinator of the activities of member state agencies, such as the Medicines and Healthcare Products Regulatory Agency (MHRA) in the United Kingdom.  

That is about to change. Starting in November, EMEA will be able to approve drugs conditionally, requiring further safety studies to be carried out before the product is given a full license. In a similar vein, the United Kingdom's Department of Health is investigating the possibility of introducing a further tier of trials before full registration is permitted. A drug would be given a limited license to be used in a wider population of patients, under close monitoring.  

In an attempt to improve pharmacovigilance, the United Kingdom has already announced changes to its "yellow card" scheme. Set up in 1964 in the aftermath of the thalidomide tragedy, the system requires doctors to fill out cards when patients experience adverse reactions to medicines. The cards are torn out of the back of the prescribers' "bible," the British National Formulary (BNF), then sent to the government's Committee for the Safety of Medicines. Newly approved drugs are flagged in the BNF with black triangles, prompting doctors to keep a close eye on them.       

A recent amendment to the scheme allows doctors to post details of suspected reactions online and encourages patients to report adverse events themselves. MHRA will publish anonymous data on suspected ADRs on its website, which will be available to the public. 

Although all medicines have safety issues, risks have to be balanced against potential benefits. The serious side effects of some cancer drugs, for example, would not be tolerated in a product to treat, say, depression.  

In the current climate, there is a danger that the careful balance between risk and benefit may be upset. Serious side effects with very low incidence, such as those seen with Vioxx, are unlikely to show up until the drug enters widespread use. Although close monitoring is essential, an over-cautious approach would lead to the delay of medicines that offer huge benefits to patients. 

The pharma industry, although it has generally welcomed the more careful monitoring of side effects, is concerned with the idea of having approvals and safety monitoring carried out by separate entities. "I think to focus on safety is important. But the outcry that we should have separate safety and efficacy evaluation units is not a good trend," says Tachi Yamada, GlaxoSmithKline's chairman of R&D.        

Pharma companies in Europe believe it already takes too long for new medicines to reach patients. When a drug has been given EU approval, it will not be available to patients in the different member states until local health authorities make final decisions about issues such as reimbursement. Separate bodies for efficacy and safety will likely lead to further delays by adding another layer of bureaucracy. 

The European Federation of Pharmaceutical Industries and Associations, which represents the pharma companies, has said it will issue its own proposals this year for post-marketing surveillance of pharma products. But there remains a huge amount of public concern about whether the medicines doctors prescribe are safe. There has to be a happy medium between risk and benefit, but working out where that line is, particularly in light of knee-jerk reactions to high-profile withdrawals, will not be easy. And a separation of efficacy evaluation from safety monitoring would only make that harder.

 globalcorrespondent. She can be reached at 

Articles

World News

Pharma companies in Europe believe that it already takes too long for new medicines to reach patients. Separate bodies for efficacy and safety will lead to further delays.

Global Report

In 1999, The world was banging on the industry's door

 for free AIDS drugs. With one hand, activists pummeled companies' intellectual property, their prices, and their access programs, and with the other, painted antiretroviral (ARV) drugs as the single magic bullet for solving the worst scourge to ever face mankind. 

  Views from Uganda's Queen Elizabeth National Park, Uganda. 			

The idea that free AIDS drugs wasn't the answer fell upon deaf ears, and the industry struggled to define its role in what was essentially a gruesomely massive public health and economic problem. Out of those troubled waters grew corporate social responsibility programs of unprecedented scope. Companies took a radical approach: instead of free drugs—an unsustainable donation given the scope of the problem—they wanted to invest in African systems that could grow and multiply and allow governments to treat their own people.   			

That year, Bristol-Myers Squibb (BMS) implemented its ambitious $115 million public health plan that reflected the enormity of the task at hand. The program, Secure the Future,  targeted nine African countries—places like Burkina Faso and Lesotho—to begin developing the infrastructure needed to respond to and cope with the pandemic. 

A lab technician at work in an African clinic funded by Secure the Future. 			

Secure the Future inspired other companies to go forward with their initiatives—and they did. The industry responded to AIDS, malaria, and tuberculosis with more than $2 billion in aid in 2003, surpassing the annual budgets of development partners like the World Health Organization (WHO) or UNICEF, according to the Hudson Group. Many of those programs, like BMS', were five-year commitments. That means company initiatives now stand at a critical point, where their futures are being decided. 			

 offered a snapshot of ARV distribution in Africa and the obstacles organizations face in obtaining drugs. This article discusses the road forward—how companies are developing new models, scaling up programs, and teaming up to fashion a better tomorrow for Africa.  

 Views from Uganda's Queen Elizabeth National Park, Uganda. 			

Back in 2001, Dr. Peter Mugyenyi was busy making secret arrangements to bring the first shipment of generic ARVs into Uganda. After researching doses, quality and cost, he decided to purchase the drugs from the Indian generic manufacturer Cipla. However, Cipla balked at the request: At the time, 39 drug companies were fighting the government of South Africa in court, contesting what they felt was their right to compulsory license ARV drugs. Mugyenyi wasn't a licensed importer, but he told Cipla to send the drugs anyway—he would take full responsibility for the consequences. 										

Mugyenyi never landed in court. But his actions, and those of others like him, helped create a new era of intellectual property laws and mores in treating AIDS. Later that same year, companies dropped the court case in South Africa and began to license ARVs to generic manufacturers for use in the developing world. GlaxoSmithKline (GSK) gave South Africa's Aspen Pharmacare permission to manufacture and distribute Retrovir (zidovudine), Epivir (lamivudine), and Combivir (zidovudine/lamivudine). The following year, Boehringer Ingelheim (BI) issued Aspen a license to produce Viramune (nevirapine).  

BMS chief executive Peter Dolan meets residents of the KwaZulu Natal Province, South Africa, in an AIDS awareness event.			

Those licenses would prove vital in the next round of debate over access and patents, which came when President Bush's Emergency Plan for AIDS Relief (PEPFAR) was implemented in 2004. The program, a five-year $15 billion initiative to combat HIV/AIDS in 15 target countries, aims to increase ARV usage, especially in Africa. But the US government said PEPFAR must buy FDA-approved products—there was to be no quality double standard for rich and poor patients. They also said that generic ARVs would be eligible for purchase only where they did not violate patent rights. The sum of that equation meant PEPFAR used brand-name drugs only. 

The situation changed in January 2005, when FDA granted tentative approval (given when patents or marketing exclusivity are still in effect in the US) to Aspen's co-packaged offering of lamivudine/zidovudine and nevirapine.  

Some industry initiatives include home-based care as part of larger community-based programs for rural populations.

Activists hailed the approval as a major advance. They believe local manufacturers can produce AIDS drugs cheaper than brand-name companies because they have lower labor costs and because they've learned efficiency by working with low-margin products. Mark Isaac, vice president of the Elizabeth Glaser Pediatric AIDS Foundation, estimates the co-packaged treatment's price at $16 to $20 a month, less than half of the $55 "no profit" price that he pays for the same drugs from the research-based industry. The drugs will also be cheaper because they are exempt from the 10 percent tariff recently imposed by the East African Community's Customs Union on imported medicines, which was intended to stimulate regional trading. 

If the Aspen model works, says one Big Pharma company source, it could change the model for the developing world. Research-based companies could focus on R&D, and leave the manufacturing to generic companies. But the truth is, some serious questions remain about the Aspen model: 

 Some executives doubt that the Aspen model will actually deliver low prices. They remember President Bill Clinton's HIV/AIDS Initiative, which promised to obtain steep discounts on ARVs by working closely with generic manufacturers. However, at a meeting with NGOs and the Indian generic firms in January, many procurement professionals say they haven't been able to obtain the "Clinton price."  

 Just because a company produces drugs cheaply, consistent supplies are not guaranteed. 

"Generics are usually available today, but tomorrow you're not sure," says Joseph Saba, CEO of Axios, a consulting firm that implements the industry's programs in Africa. "People who work with generic usually end up buying brand drugs while waiting for deliveries of generic," he says. 

Brazil and Thailand have both called on the pharma industry to supply ARVs when copy manufacturers couldn't fulfill their tenders. But in Africa, where the demand is so great, pharma might have a difficult time picking up the slack. Without better coordination of supply efforts, those hiccups can pose a real and present danger for patients that the drugs won't arrive as planned.  

Companies have to dedicate in-house resources to ensure that licensees maintain the promised quality. The big concern is that poor-quality drugs will lead to increased resistance. Secondary concerns are that low-quality licensed generics might dilute brand value or harm companies' reputations. 

 As with any new market dynamic, executives involved with licensing must rewrite existing business rules. GSK, for example, licensed several AIDS patents to Kenyan-based Cosmos, but is just now negotiating what the generic's name will be. 

There are also questions about how both brands will work in one market. "Here we are licensing for exactly the same territories and indications for which we are supplying and marketing our product," says Jon Pender, GSK's director of global access issues. "It's new for us to do it this way." 

Although licensing (and the Aspen deal) give the impression that pharma's intellectual property is being respected, there are strong signs that it will not be for long. Marie-Paule Kieny, director of WHO's Initiative for Vaccine Research, recently stated that, when an HIV vaccine is finally developed, it will be made widely available irrespective of patent rights.  

That may sound like a promise to patients. But to private-sector companies, it's a warning. Some research suggests that the push for access is causing companies to silently back away from AIDS research. According to American Enterprise Institute's Roger Bate, 80 companies conducted AIDS-related research five years ago. Today, only 60 do. Some of that might be explained by industry consolidation, but the policy environment probably plays an important role as well.  

Merck went into Botswana in 2000 with good reason. In this small, relatively well-off and politically stable country, 38 percent of adults were infected with AIDS. The government had  stalled, unable to combat the the situation with few hospitals, clinics, or professionals trained to treat AIDS patients—they hadn't even mapped out how they planned to fight the epidemic. In short, if there was ever a place to test public/private partnerships to combat AIDS, Botswana was it. 			

What resulted is the African Comprehensive HIV/AIDS Partnership (ACHAP). Merck pledged $50 million and free drugs over five years and the Bill and Melinda Gates Foundation donated another $50 million, to kick-start a response to AIDS in that country. 

Brad Ryder, ACHAP knowledge support manager, says the program gets at the heart of knowledge transfer: "What if you helped governments, gave them enough resources, and made HIV drugs free of charge? How would that country then go about fighting, tackling, and turning around the AIDS epidemic?" 

As of December 2004, 28,000 people in Botswana received ARVs as part of ACHAP's free drug program. That's a huge accomplishment. But for Merck, and other companies doing development work in Africa, the greatest challenge lies in leveraging the learnings of individual programs into a much broader anti-AIDS strategy. 

Although the number of patients on ARVs is growing (next year more than a million patients will access those drugs in Africa), it's no match for the increasing rate of infection. In that context, it would be easy to dismiss pharma's demonstration programs as irrelevant "islands of excellence." But, aside from treating people today, these initiatives provide treatment models for tomorrow. 

"Pharma initiatives should be sustainable, scalable, and replicable," says Trevor Neilson, executive director of the Global Business Coalition on HIV/AIDS, which leads corporate involvement in the AIDS crisis. "My biggest fear is companies will say, 'We don't have much to show for these five years except the people we served and the programs we built. We haven't been able to replicate. We haven't been able to scale up,'" he says.  

				Neilson worries less about drug and medical supply donation programs than about cash-heavy programs like BMS'.

Secure the Future's John Damonti, president of the BMS Foundation. echoes those concerns. "At the conclusion of the community support programs, there can't just be six well-operated communities on HIV/AIDS. Those have to be models for larger expansion across the country." 

So what models allow for rapid expansion? One that has gained attention is the Baylor International Pediatric AIDS Initiative, which includes a network of ten clinics. The concept dates back to 1996, when Mark Kline, MD, of the Baylor College of Medicine visited Romania and saw the desperate plight of children with AIDS there. With funding from Abbott's Step Forward program, Kline rebuilt the crumbling Constanta Municipal Hospital. And within just a few years, mortality rates in HIV-positive children dropped from 15 to three percent. The clinic worked so well that Abbott funded centers in Tanzania, Burkina Faso, and India—and expects to announce another clinic in Africa shortly.  

"Mark's work in Romania could be considered an UNAIDS best practice case study," says Reeta Roy, divisional vice president, global citizenship and policy at Abbott. "We must create as many Romanias with as many people as possible to create the strongest impact." 

Back in 2000, the Accelerating Access Initiative (AAI) brought together competing companies to figure out how to reduce the price of ARVs in nations hardest hit by AIDS. Today, almost half of all patients that access ARVs in Africa do so through AAI programs—a testament to what companies can do when they work together. Other organizations also broker company relationships: 			

Partnership for Quality Medical Donations

 Twenty-one organizations, including 10 pharmas, comprise this membership organization that is dedicated to raising the global standards for product donations.  

 This group focuses on bringing business into the fight against AIDS and includes a special section for healthcare companies.  

Companies have also been creating alliances on their own. Merck went into Romania early on to establish a foundation to the fight: their funding helped health authorities understand the scope of the disease and develop Romania's first national AIDS treatment guidelines. Abbott leveraged that groundwork by funding Mark Kline's pediatric AIDS clinic there. Then, BMS decided to build two new clinics in Africa, working closely with Abbott to replicate the Romanian model's success.  

Abbott has also worked closely with BI, in a venture where BI donated Viramune and Abbott donated the Determine rapid HIV test. "That's an example where each company had a tool to help NGOs cut the risk of mother-to-child transmission of AIDS," Roy says.   

Despite these joint efforts, there is still more work to be done. "Companies work with groups based on the relationships they cultivate," says Dickson Opul, MD, who treats the HIV-positive working population in Uganda. "We don't see the effort as AAI, but as individual companies." 

To push programs to the next level, companies must work together to create common strategies and shared world views. In doing so, they can secure their places as both innovators and global citizens by offering help to policy makers, who must tackle even bigger, more systemic issues like poverty reduction and free trade. 

Special Reports

If the Aspen model works, it could change the model for the developing world. Research-based companies could focus on R&D, and leave the manufacturing to generic companies.

AIDS in Africa: The Road Forward

In designing clinical trials, the pharma industry 

has been primarily concerned with a drug's efficacy, and therefore, modeling and simulation technologies used for those designs have also focused on efficacy. But the clinical utility and economic worth of a compound depends on many dimensions beyond efficacy, including important influences such as target population, product formulation, and patient compliance. To enhance market share and value to patients, pharma companies must consider those dimensions earlier in the drug development process.   

One way to do that is with the use of a clinical utility index (CUI), which quantifies factors like a product's efficacy, safety, cost, and contribution to quality of life—and makes trade-offs transparent to decision makers. A CUI provides a single metric for multiple dimensions of benefit and risk and captures expert opinion on the therapeutic importance of various product characteristics. It also enhances communication between discovery, development, and the commercial side.  

Getting the right information to physicians about the best clinical use of a drug becomes more challenging as the number of available therapies grows. In his article "Choosing Which Drug to Prescribe" (

, 6 August 2003), Tomas Kramer, MD pens: "Recently, a great deal has been written urging clinicians to practice 'evidence-based medicine,' in which clinical decision making is based on scientifically derived data. The problem with this, of course, is there is very little evidence upon which to practice evidence-based medicine." 			

A prescribing physician must choose a therapy that gives the best balance of efficacy, side effects, safety, ease-of-use, and quality-of-life benefits for a given patient. Analytic tools developed in pharmacological science and operations/market research can organize knowledge from different sources into a decision making framework. (See "CUI Model" below.) First, modeling is used to predict, design, and learn. A drug candidate's likely clinical performance is modeled using information from related therapies as well as pre-clinical and early clinical data. Next, the predicted product profile(s) are evaluated using the CUI.    

 Every medical therapy has benefits and risks. The relative importance of these characteristics depends on the disease, patient, and how the drug is used (for example, dosage or concomitant therapy). A CUI is a transparent means of weighing and quantifying a compound's trade-offs. It provides a scale to compare product profiles and measure the impact of scientific and market assumptions. It can be used at low cost  (a small amount of time and effort on the part of the drug development team) and early in a clinical program (Phases I and II)." 

Clinical utility is defined as the net benefit of treatment to the patient as perceived by the prescribing physician or a surrogate decision maker such as an HMO making formulary decisions. A CUI quantifies the contribution of each attribute in the product profile (label) using physician preference data, if available, or by relying on clinical advisors and other internal expertise. The latter is less expensive, and may be more appropriate early in a development program. 

 When modeling prescribing physician behavior, a CUI is similar to models used  in later clinical development (Phases III and IV). Both CUI and conjoint analysis attempt to weigh the relative value of treatment attributes and to capture that information in a single metric for comparison of competing treatment options. A CUI differs from conjoint and discrete choice analyses in its source of information and cost. Tools such as discrete choice analysis actually survey a large number of physicians asking them to choose between hypothetical product profiles. The trade-offs among elements of the competing product profiles are inferred from physician responses. A similar tool goes by the name of "conjoint analysis." Both tools use slightly different methodologies to arrive at the same empirical result and a large number of physicians must be interviewed to obtain a meaningful model, leading to high cost.  

CUI, in addition to lower cost, offers specific benefits when used in lieu of or as an early measure of physician prescribing behavior. Construction of a CUI leads the development team to identify those product attributes critical to the patient. A CUI focuses development team efforts on exploring the most valuable region of treatment—not necessarily the most efficacious—and the best market position. Further, CUI can be used to examine differences between internal team opinion and outside physician input. Multiple CUIs can explore the potential influence of non-prescriber decision makers, such as the FDA or third-party payers. 

In clinical practice, the patient's decision maker is generally the prescribing physician. Ideally, the development process will result in drugs that are just what the prescribing physician ordered. The framework for the CUI is elicited from the project team. Attribute utilities and weights are determined based on physician preference data, if available, or internal expert opinion. When combined with models of what the body does to the drug (pharmacokinetics) and what the drug does to the body (pharmacodynamics), the CUI is a tool for understanding the benefit of the drug to the patient, relative to competing therapies.  

Because these models also include the uncertainty in the drugs effects, they can also be used to predict the outcomes of proposed development trials. As a development program progresses, ongoing or completed trial results provide learning  and models are updated. Model output can be broken into categories that show the chance of achieving a given product profile and CUI, given what is known about the drug. The chances of different product profiles can, in turn, be linked to financial models for decision making.   

Such models have been used successfully to support better choices in clinical development, as illustrated in the following case studies. Each is derived from a real project conducted for a client in the pharmaceutical industry. Indications and other information may have been blinded to protect confidentiality. 

CUIs needn't be complex to prove useful. A simple index, constructed using a penalized dose-response model, was used to explicitly value trade-offs between increased efficacy and side effects for a new chemical entity (NCE) with a novel mechanism of action. This index formed the basis for the choice of best dose, which was in turn used in simulations to optimize trial strategy for a phase II dose-ranging trial.  			

The compound was a psychiatric medication with a novel mechanism of action and little prior information was available to inform expectations for efficacy or side effects. Phase I safety trials and one inconclusive Phase IIa trial had been completed, leaving high uncertainty in efficacy and dose-response for the NCE.  

A modeling project was undertaken to improve efficiency and informativeness of Phase II trial strategies, and to optimize the treatment regimen. First, drug and disease models were developed to quantify expectations and uncertainties about efficacy and side effects. This formed the basis for a penalized dose-response model, developed to provide a utility criterion for choosing best dose. (See "Dose Benefit Model".)  

A model of various dosing strategies was developed. Simulations assessed each design's performance compared to fixed-dose dose-ranging. The criteria for trial quality were: closest estimate of best dose (Dbest) and minimum effective dose (MED), as measured using the penalized dose function (utility index). The simulations indicated an advantage to particular designs because the uncertainty in safety and efficacy was understood and a utility index provided a single, quantitative measure of that best dose. 

Evaluating a potential next-in-class drug against successful predecessors requires close comparison of risk-benefit profiles. A CUI is ideal for the job.  			

A new selective estrogen receptor modulator (SERM) was in early human trials. Concern had risen over a possible side effect, endometrial hypertrophy, which could lead to cancer if unchecked. Further trials posed not only financial risk but possible health risks for hundreds of women if this side effect proved troublesome. To explore whether any dose of the new candidate could be expected to perform acceptably against the popular first-in-class drug, Evista (raloxifene), Aventis Pharmaceuticals turned to modeling and simulation.  

Dose-response models for efficacy versus side effects were developed from early trials of the new SERM and prior information on related compounds. An initial version of the CUI was elicited from project team members. They identified 10 critical attributes of the product profile. For each attribute, possible attribute levels and their clinical value were defined using a preference ratio. The attributes were ranked and their importance weighted. The team reviewed the attributes to ensure that they described all important and relevant clinical issues, captured the range of outcomes for each attribute, and reflected the expected clinical value of possible outcomes. 

Simulation produced a distribution of likely patient outcomes for each attribute. Each distribution was parsed into categories, each of which had a known likelihood of occurrence. Every unique combination of attribute levels yielded one possible CUI score. The probabilities of the attribute levels for a given CUI score yielded the likelihood of that score being the "true" product CUI. The combined set of possible CUI scores and their likelihoods were characterized as a probability distribution, describing the expected CUI values for the new SERM and its primary competitor. 

Simulations revealed that the new SERM, as reflected in its CUI distribution, was expected to perform worse than the established competition at all doses. Sensitivity analysis made it clear that the drug could have performed well except for the key side effect; an identical drug without the risk of endometrial proliferation would surpass the competition. The upcoming trial would have been quite expensive and those funds could be used more effectively on other compounds. Consequently, it was decided to progress a more promising back-up compound that did not appear to have this liability in preclinical testing.  

In early drug development, a CUI makes optimal use of internal expertise and minimizes the cost of focusing development on the best product profile—not the most efficacious one. By using comparisons to current competitors and new entries under development, drugs that have no differentiation can be weeded out earlier from a crowded marketplace, providing more resources for R&D. It can substantially lower the cost of delivering a beneficial drug to the marketplace. 			

Additional benefit is gained by the use of modeling and simulation analyses in Phases II and III. By investing in these more intensive and adaptive early phase analyses, developers can spot poor drug candidates earlier and improve positioning of those going into Phase III. The use of a CUI can optimize the trade-offs in speed, cost, and learning during these phases, leading to quicker wins. The end result is a label that supports the best therapeutic use of a new therapy, and offers the best patient benefit. Thus, the CUI is a valuable communication, decision making and optimization tool.

 or (650) 314-3843) is director of decision services, and 

 is a senior scientist, both for Pharsight. 

 is senior vice president and global head of clinical discovery and human pharmacology for Aventis Pharmaceuticals. 

The authors would like to acknowledge Shawne Neeper and T. J. Carrothers (both of Pharsight) for their efforts in developing this article.

Features

The use of a CUI leads development efforts to explre the most valuable region of treatment - not necessarily the the most efficacious.

Transparent Trade-Offs

Everybody knows about "mission creep"—the way an organization tends to gradually expand its vision of what it's supposed to do in the world, often losing focus and effectiveness in the process. These days I think I see something similar happening in the debate over drug safety. Let's call it "solution creep."  

Here's an example: As this issue was going to press, Sandra Kweder, deputy director of CDER's Office of New Drugs at FDA, testified before a Senate committee. According to news accounts, she proposed that FDA be given additional power to add warnings to drug labels—in order to avoid the sort of protracted negotiation that kept cardiac warnings off of Vioxx's labels for many months after the agency became aware of potential problems. 

On the surface, that seems pretty reasonable. Safety warnings need to be prompt. When they're not, patients face needless risks. What's more, as we saw in the Vioxx case, delays in delivering warnings can undercut the credibility of FDA, pharma companies, and the industry as a whole. Companies may not be happy to see FDA get unilateral power to impose labeling changes post-approval. (The biggest worry is that the power to change labels would reside with FDA's new safety office, and that the safety office would see its primary mission as busting the chops of the folks who approve drugs.) All in all, though, it sounds like a reasonable solution. 

But solution to what? Remember, Merck and FDA may have been slow in putting revised safety information on Vioxx's label, but they did eventually put it there. The question is whether patients and doctors actually read and used it the way they're supposed to.  

If they didn't—which is how it looks to me—then getting the warning into people's hands a little earlier will do next to nothing to improve patient safety. Kweder has proposed a good solution, but to the wrong problem. 

That's how solution creep works. As we start to deal with a complex problem, people start putting solutions on the table. The solutions make sense, they advance goals we believe in, and before we know it, we're committed to them, whether they solve the problem or not. Full disclosure of clinical trials? Let's go for it. Drug safety office? Why not? Pretty soon, the solutions are driving the discussion. We forget what we were trying to accomplish. 

The assumption behind many of the "solutions" I'm hearing these days is that we have a drug safety problem, and that people need more information. I think the real problem is different: We have a drug safety system based on the idea of letting patients and doctors decide how much risk they want to face. And for whatever reason, that system isn't working. Legislators, patients, and doctors alike all show signs that they don't understand it, don't like it, and aren't living up to the level of personal responsibility it requires.  

That's a big problem that we're not going to solve by throwing solutions at the wall and seeing which ones stick.  

It's tough to say no to solution creep. The credibility of pharma and FDA has clearly taken a hit, making it hard for either of them to get up in front of the public and say, "Wait, these proposals are fine, but they don't do the job we need to do 

But someone needs to start taking that stand. 

The stakes are high. The states are clearly unhappy about drug regulation and are starting to write laws regulating marketing. (A list appears) Louisiana, troubled by the Vioxx advisory panel's decision, plans to introduce its own prescribing rules for the drug. Centralized drug regulation is vital for pharma. So is the informed-risk approach behind the current system. If we let them creep away, the industry may find itself with problems to which there are no solutions at all.  

From the Editor

In the drug safety debate, we're hearing plenty of potential solutions. They're smart and advance desirable goals. There's just one thing wrong with them: They don't solve the problem.

 an anti-counterfeit solution would provide protection throughout the supply chain, allow for easy product identification by physicians, pharmacists, and patients, be easily implemented without ongoing costs—and improve brand image and marketability while it's at it. Yet most current anti-counterfeiting measures involve packaging technologies such as holograms, inks, bar codes and radio frequency ID (RFID) that, although useful, cannot ensure the integrity of the pharmaceutical supply chain, because drugs do not remain in their original packaging. Legitimate repackaging regularly occurs in the pharmacy and elsewhere, and authentic packaging—recycled or stolen—can contain adulterated, counterfeited drugs.   

 No single anti-counterfeiting technology can provide adequate protection. Pharma's objective must be to design products and packaging with features that are  so hard to duplicate that counterfeiters will turn their sights elsewhere. 			

It is, after all, the counterfeit medications, not the containers, that are harmful to patients and costly to manufacturers. For tablet manufacturers, the solution is to modify the medication itself with on-tablet technologies that make pills difficult to fake but easy to identify. These technologies are also cost-efficient and stay with the medication from the factory to the patient.   

A great number of counterfeits have been uncovered by patients and pharmacists who noticed that the tablet's color, shape, size, or taste was different from what they had experienced before. Several pharma companies have reported that a majority of the calls they receive from consumers questioning whether they have a counterfeit product are triggered by some type of sensory response related to the dosage form itself. A patient's personal detection system consists of eyes, nose, mouth, and hands, so a tablet's unique visual appearance, aroma, taste, or texture is important.  			

Many patients, especially the elderly who tend to take the most oral medications, often have trouble identifying drugs by reading labels, so this type of sensory identification helps protect patients at the point just before they consume the medication. Each individual sensory identifier on a tablet significantly enhances the likelihood of a patient calling the manufacturer, or their pharmacist or physician to question the authenticity of a medication.  

With pearlescent coatings, a rainbow of colors is possible. These colors can only be duplicated by knowing the specific pigment grade combination and the processing procedures used in the drug's manufacture. They cannot be reverse engineered. 			

Simple visual and sensory means of identifying drugs can aid patients with compliance and safety. When patients can readily identify the right drug, they are more likely to take the right drug. A standardized tablet imprint system, for example, that identifies the dosage strength and name of a drug, combined with readily available information resources for patients and pharmacists, would help prevent many medication errors. 

A United States Pharmacopeia (USP) survey on standard imprint codes drew the following comments from pharmacists:  					

"We should be inventing a system where a patient would be able to identify a tablet."

"The difficulties come in identifying tablets or capsules without any markings. They may be OTC or one of the many generics that are white, typically round, biconvex shaped."

"The lack of a standardized and easily identifiable code on many medications makes the identification process too cumbersome. A national standard should be adopted. In addition, a manufacturer's unique identifier should also be employed to distinguish particular brands or products."

The United States has the safest supply of drugs in the world—when they are acquired through standard distribution channels. However, the public now encounters increasingly aggressive internet marketing that falls outside of the normal physician/pharmacy supply chain and is a ready outlet for the distribution of counterfeit or illegal drugs. The actual size of the US internet counterfeiting problem is uncertain.  But according to a September 29, 2003 FDA News report, an estimated 80 to 90 percent of these products do not meet US regulatory requirements, and more than 40 percent of the drugs coming into the US through the internet, from countries such as Mexico, are fake. (For more information about counterfeit drugs, see "Resources".)  						

Both FDA and Congress are now relying on pharmaceutical companies to design their packaging and products in a manner that deters counterfeiters. The responsibility of finding innovative methods of ensuring the security of the nation's drug supply is being put squarely on the shoulders of pharmaceutical manufacturers.  

On January 15, 2004, a congressional letter was sent to major pharmaceutical companies, requesting that they provide information about the development of plans to prevent counterfeiting and diversion of their products. Congress also wanted to know what actions and countermeasures were being taken relating to specific products being marketed by the illicit internet sites of foreign pharmacies. 

At the same time, FDA plans to publish a guide about notification procedures for changes made to products, packaging, or labeling for the purpose of detecting and deterring counterfeit drugs. Regulatory hurdles to making these specific types of changes are now being lowered.  

With high-definition imaging technology, coded images can be designed into logos,  acting as fingerprints that make tablets difficult to duplicate. 			

No single anti-counterfeiting technology can provide adequate protection. Pharma's objective must be to design products and packaging with features that are so hard to duplicate that counterfeiters will turn their sights elsewhere. Fortunately, there are many proven on-tablet technologies available today that can make drugs difficult to fake but easy to identify. These technologies include: 					

visual identification—unique colors, shapes, sizes and logos

chemical identification—edible markers in the film coating

sensory identification—flavors and aromas with a unique profile

Round, white, uncoated, debossed tablets are easy to copy and cheap to produce. A tablet press is all that's needed. On the other hand, unique colors, sizes, shapes, and high-definition logos can aid in quick and accurate identification of tablets, making counterfeiting extremely difficult. The more technologies that are used, the more difficult they are to counterfeit. 			

New pearlescent coating technology allows pharma manufacturers to visually distinguish their products from counterfeits and other drug products. The uniquely colorful pigments created with this technology all meet current 21 CFR colorant regulations and are custom-produced to exact specifications in a single-use, GMP facility, the only one of its kind in the US. Because this technology is only available through controlled channels, the opportunity for counterfeiters to gain access to pearlescent pigments anywhere else in the marketplace is effectively eliminated.  			

With pearlescent coatings, a rainbow of colors is possible. These colors can only be duplicated by knowing the specific pigment grade combination and the detailed processing procedures used in the drug's manufacture; they cannot be duplicated by using analytical or reverse-engineering techniques. Several products using this technology are in clinical trials and should enter the market by 2007.  

Any number of colors and images can be achieved with the same chemically stable, inert, light-refracting ingredient, both qualitatively and quantitatively, by controlling processing variables. Various coating systems are available that can give the same pearlescent effect while meeting each country's regulatory requirements.  

As an additional benefit, the ease of visual identification by caregivers, pharmacists, and patients can reduce medication errors by ensuring that the right tablets are taken appropriately. Although the current FDA bar code regulation only addresses medication errors that occur in the hospital, visual identification methods are effective throughout the supply chain, right to the patient at home.  

Typical costs to use this technology are minimal and can range from 0.02 to 0.04 percent of drug revenue. So, for a typical $1 billion blockbuster product, a nominal annual cost of $200,000 to $400,000 would enable these technologies. This represents a technology investment of $0.001 per tablet, based on a selling price of $3.00 per tablet.  

Innovative electronic technology now allows manufacturers to use common, edible inks to apply two-dimensional (2D) Datamatrix bar codes directly on the tablet surface. Smaller than their linear counterparts, 2D bar codes can be used to code specific information such as National Drug Codes, which provide identification control all the way from the manufacturing plant to the bedside. Plus, the unique bar code technique used in this process cannot be easily duplicated.  			

Tablet bar coding restricts the potential for error even after the tablet has been removed from the packaging, either for delivery to the patient's bedside or for repackaging. During bulk repackaging operations, bar code GMP controls can now be implemented to assure that there is no chance for mix-up, either in the packaging or the dispensing. 

High-resolution imaging now provides a wide range of new identity options. Tablets can contain images with bar codes as small as 2.5 millimeters that are readable by typical high-resolution bar code scanners. For easy identification by patients, readable numbers, codes and logos can be combined with bar codes. With high-definition imaging technology, coded images can be designed into logos, acting as fingerprints that make tablets very difficult to duplicate. These images may also be made scannable to provide visually appealing electronic identification.  

High-definition imaging can also be combined with number codes to make tablets highly recognizable and even harder to counterfeit. Multi-coded tablets can be easily traced through the supply chain, and pharmacists and physicians can readily identify individual drugs that patients present for verification. Some products currently in Phase II are being developed with this technology.  

Incorporating covert chemical markers into the film coating of tablets adds even greater security against replication. Taggants—simple, stable, inert, organic chemicals that are present in the product in trace quantities—can be added to film coating solutions under tight security during product manufacture. Undetectable by the human senses, taggants are also difficult, if not impossible, to detect through normal analytical techniques and cannot be copied or removed from the dosage form. Available with wide regulatory acceptance, manufacturers can include taggants in new products or incorporate them into existing products with minimal regulatory requirements.  			

Because they are detected through the use of a specific recognition molecule and can be quantitatively measured using inexpensive equipment, taggants are also being used as chemical bar codes. With this methodology, manufacturers can provide additional information (such as manufacturing location) that goes beyond the data available in the 2D electronic bar code on the tablet surface. Robust taggants provide immediate chemical authentication when tested by pharmacists or customs agents using in-field testing kits. 

Specialized flavors and aromas incorporated into tablet film coating systems can also provide unique characterization profiles identifiable by patients. In addition, they act as covert forensic fingerprint profiles that can be tracked and traced. Flavors and aromas can be difficult to duplicate because oxidation can change the sensory profile if counterfeiters do not use the same stable grade that is in the genuine product. And it is difficult to identify the specific grade used in an individual drug. 

A whole palette of globally compliant flavors and aromas for use in tablet film coating systems has been developed. Not only are these sensory additions recognizable by humans, but aroma and taste scanning detectors also are available for electronic identification of specific aroma and flavor profiles.  

On-tablet technologies not only protect against counterfeiting and product diversion, but they also create a higher profile image that can enhance branding and marketability. Two of the best known Rx examples are Nexium, the purple pill, and Viagra, the blue diamond-shaped tablet.  Much as the Coca Cola bottle was the first US trademarked object, a uniquely designed Rx product can be established as a trademark globally.  This serves to maintain the uniqueness of the tablet design. Not to mention, the visual branding of a tablet reinforces the product identification with patients every time they take the medication. 			

Before incorporating these technologies into their products, pharma companies may ask: What type of change notification requirements will there be with the FDA?  Here's a summary of regulatory information for each technology: 			

 FDA's Scale-up and Post-Approval Changes Guidance for Immediate Release Products (SUPAC-IR) Level 1 allows for the deletion or partial deletion of a colorant and allows the film coat weight gain to vary by up to one percent. The addition of a pearlescent coating to a tablet, adding less than one percent weight gain, would involve a qualitative change, but there would be no effect on tablet dissolution. Such coatings can provide a multitude of colors with the same pigment chemistry, allowing for the same label claim for different colored tablets. 

 SUPAC and FDA guidance for changes to a new drug application or supplement application (NDA/ANDA) already allow for the addition or modification of a code imprint when the ink components have been previously used on an approved drug. 

 FDA has said that a trace marker can be added to the coating of an existing IR solid oral dosage form with the only requirement being notification to FDA. The markers must be either a GRAS (generally regarded as safe) substance or an inactive ingredient already present in a CDER-approved product. The addition of parts-per-million or parts-per-billion levels of food or excipient grade markers to a film coating on an existing drug should not affect drug dissolution.  

 Supac-IR allows for the deletion or partial deletion of a flavorant as a Level 1 annual reportable change. Flavors are typically added at low levels into the film coating and have minimal contact with the drug, therefore, the addition of a flavor is not likely to affect dissolution. 

Here are a few sources for more information about the prevalence of counterfeit drugs.

, "Vulnerability to Counterfeit Drugs," May 2004, available at: http://

, "FDA/U.S. Customs Import Blitz Exams Reveal Hundreds of Potentially Dangerous Imported Drug Shipments," September 29, 2003, available at: http://

www.fda.gov/bbs/topics/NEWS/2003/NEW00948.html

, "Counterfeit Drugs—Sophisticated Technologies and Old-fashioned Fraud Pose Risks to the Prescription Drug Supply in the U.S.," November 10, 2003 

, "Pharmaceuticals Drug Threat Assessment," November 2004; available at: http://

www.usdoj.gov/ndic/pubs11/11449/diversion.htm

In an ideal world, an anti-counterfeit solution would provide protection throughout the supply chain, allow for easy product identification by physicians, pharmacists, and patients, be easily implemented without ongoing costs-and improve brand image and marketability while it's at it. Yet most current anti-counterfeiting measures involve packaging technologies such as holograms, inks, bar codes and radio frequency ID (RFID) that, although useful, cannot ensure the integrity of the pharmaceutical supply chain, because drugs do not remain in their original packaging. Legitimate repackaging regularly occurs in the pharmacy and elsewhere, and authentic packaging-recycled or stolen-can contain adulterated, counterfeited drugs.

More Than Just a Pretty Color

In his first few days as secretary of the Department of Health and Human Services, Mike Leavitt made waves by announcing plans to revise Medicaid and ensure drug safety. But the "main event" of the year, he emphasized, will be the implementation of the Medicare Part D prescription drug coverage program. The White House has a great deal at stake in persuading insurers and pharmacy benefit managers (PBMs) to set up prescription drug plans (PDPs) in all 34 Part D regions-and in getting seniors to sign up for coverage. The industry has much to lose if the program fails to emerge as promised, so pharma companies plan to use their PR resources to help Medicare beneficiaries understand and join the program. Marketers already are discussing discounts and rebates with PDPs, which face tight deadlines for getting their packages in place.

The Part D application and bidding process begins this month. Plans have to submit Part D applications to the Centers for Medicare and Medicaid Services (CMS) by March 23 and file formularies next month. That gives CMS a month to review the proposals in order to launch a bidding process in June and award contracts in September. PDPs will start marketing their plans and enrolling seniors in October. For plans to establish formularies and calculate bids, they will need to know what deals manufacturers will offer.  

The CMS Part D final regs, which were issued on January 21, spell out procedures for implementing this massive program. (See 

, "Medicare Drug Benefit," February 2005.) But as the  industry and healthcare community digest the regulations-more than 1,100 pages on the drug benefit alone-several thorny issues have emerged that will shape pharma participation in the program and its likely impact:       

Manufacturers have been expanding programs that provide drugs to low-income patients at no or low cost, but companies will face new challenges in structuring these patient assistance programs to fit Part D. One key problem: Free drugs provided to seniors do not count as true out-of-pocket (TrOOP) costs-and TrOOP costs have to reach a certain level (about $3,600) for a beneficiary to qualify for catastrophic coverage. A possible solution lies in the fact that CMS regs permit state pharmacy assistance payments to count for TrOOP, an approach that marketers consider necessary to continue PA programs  for seniors. 

Beneficiaries may be hit twice if they have to pay for non-formulary drugs. Not only do they lose co-payments, but their outlays do not count as TrOOP for reaching the catastrophic floor. The policy puts a lot of pressure on patients and doctors to file for exceptions to gain coverage for non-listed medicines. 

Plans have to tell beneficiaries which drugs they cover, but not necessarily which drugs fall into which co-payment tiers. CMS plans to issue marketing guidelines in April to clarify this and a host of disclosure and coverage issues. 

Off-label drug use, of course, is always a thorny issue, and CMS is trying to walk a fine line between supporting coverage of appropriate off-label uses and allowing PDPs to limit excessive prescribing. CMS acknowledges that physicians can prescribe drugs for off-label uses and says it will weigh whether plans erect barriers to off-label prescribing in evaluating a formulary program. But the Part D rules specify that PDP formularies don't have to cover off-label drug uses and don't have to establish classes where there is no FDA-approved drug. The pressure is on pharma companies to document the benefits of off-label uses to get them listed in appropriate formulary categories. 

In formulary negotiations, marketers often offer services to PBMs, but such arrangements with PDPs may raise anti-kickback charges. Pharma companies will have to carefully structure disease management, drug utilization review, and other services, particularly if such activities replace discounts and are too much above market value.  

The U.S. Pharmacopeia wants CMS to assign it a formal role in evaluating its formulary guidelines over the next few years as new drugs enter the market and new information emerges about the safety and efficacy of existing therapies. A lot of manufacturers are unhappy with the USP guidelines and oppose their continued influence over the program, but CMS will need some independent body to provide ongoing review after the program is established. 

CMS already conducts parallel reviews of some medical products covered by the traditional Medicare program. These reviews enable the agency to issue speedy decisions about coverage when FDA approves a new product for market. It is reasonable to expect that over the next few years CMS will play a much larger role in monitoring drug safety, marketing, and appropriate use. CMS data banks will provide a wealth of information on drug utilization and adverse events and may shape development of risk management plans for high-risk drugs. CMS coverage for seniors participating in clinical trials may shape research protocols.  

All these issues will affect the overall cost of the Medicare Prescription Drug Benefit, which continues to generate outrage on all sides. When Congress approved the Medicare Modernization Act in December 2003, the administration insisted that the cost would be about $400 billion over 10 years. The CMS actuary quickly boosted the number to $534 billion, which raised an outcry. Those fairly high numbers applied to the 10-year period of 2004 to 2013, which includes two years before the program even starts.        

Now fiscal conservatives and Democrats are up in arms over the latest soaring administration cost projections for Part D: a whopping $724 billion for 10 years, from 2006 to 2015, when more seniors are expected to be enrolled in the program. Conservatives want to cap program spending at $400 billion, while Democrats insist they can save money by bringing in cheap imports and establishing a centralized Medicare drug purchasing program, unhampered by the much-debated non-interference clause.  

Of course, the Part D program won't be so expensive if seniors decide not to participate. All the current estimates assume that 90 percent of eligible Medicare beneficiaries will join the program, but most observers doubt that participation will be anywhere near that level. One hurdle in convincing seniors to sign up is considerable uncertainty about future co-pays and costs. CMS expects monthly premiums to average $35, but that's just a guess. And if CMS finds itself spending more on drugs than anticipated, the statute calls for adjusting Part D parameters, including benefit ceilings, the catastrophic floor, and levels for co-pays and deductibles.  

A broad range of beneficiaries need to join the program for it to work, but it's not yet clear how to measure success or failure. Should policymakers expect 90 percent of seniors to enroll in PDPs-or will 75 percent be a reasonable expectation? Will the program have to keep spending down to $400 billion a year, or will someone figure out how to relate increased spending on drugs to broader measures of health care quality? One thing is certain: The more seniors in the program, the more it will cost. We can't have it both ways.

 One important but less noticed provision in the Medicare program exempts PDP rebate negotiations from the Medicaid best price policy. Now it looks like best price requirements may disappear completely.

The provision grew out of a business challenge posed by Medicaid: Companies were required to give Medicaid their best price, but if that price was revealed publicly, it would quickly be used by other customers to force down the prices they already paid. Instead, the government set up a rebate system based on Average Manufacturer's Price and the best price offered to any customer (with a few exemptions, such as the Veterans Administration). HMOs and hospitals have complained for years that best price essentially puts a floor on the prices they can negotiate. CMS administrator Mark McClellan evidently agrees and proposes to switch to a flat rebate formula. Pharma companies are not too upset because state Medicaid drug spending will drop considerably as low-income seniors switch to Medicare to receive drug coverage under Part D. 

McClellan doesn't expect the switch from best price to curb Medicaid spending on drugs, but it should help reduce costs for the broader health care system. The task of lowering the Medicaid pharmacy budget will come through another reform initiative. This aims to restructure Medicaid pharmacy reimbursement to base payments on drug acquisition costs instead of wholesale prices, similar to changes made in how Medicare pays for drugs administered by doctors and hospitals. This reduction in "overpayments" to pharmacists, together with proposals to close loopholes that permit excessive payments to states and allow some wealthy seniors to  qualify for assistance, are projected to cut Medicaid spending by $60 billion over 10 years.

Washington Report

Should policy makers expect 90 percent of seniors to enroll in PDPs, or will 75 percent be enough? Will the program have to keep costs down to $400 billion a year, or will spending be linked to savings elsewhere?

Washington Report: The Main Event Begins

 talks to the newly appointed leaders of the industry's most influential advocacy organizations.  

PhRMA's new president is tasked with making politically-charged issues non-partisan, and positioning the industry on the sides of patients  and doctors.  			

As president of BIO, Greenwood plans to employ three secret tools of advocacy: the truth, the truth and the truth.   			

The world has its eyes—and hopes—set on pharma's treatment models to scale up efforts to fight the AIDS epidemic. Will they be ready? The second in a two-part series.  

On-tablet technologies go further than RFID because they ensure the integrity and safety of pills throughout the supply chain, and into patients' mouths. 

The market judges drugs on more than just efficacy. Clinical Utility Indices measure these considerations throughout the development process, before it's too late. 

Government cracks down on conflicts of interest » FDA Commissioner Lester Crawford to focus on drug safety » Pharma's sales growing slower » SEC rules jeopardize vaccine stockpiles » FDA establishes drug safety panel » FDA OKs Aspen's AIDS drug for Africa. 

Pharma's bad rap just got worse » Scripts for SSRIs slowed before FDA's proposed black box warning.   

Marlene Bobka, VP of FOI Services, on the intelligence to be harvested from the Freedom of Information Act.  

Putting the Medicare benefit into practice means pharma has to tackle some thorny issues. 

European regulators consider new safety systems in response to Vioxx. 

Just because you're paranoid, it doesn't mean that they're not after you. 

India's new patent law threatens the country's generic ARV supply, a vital part of AIDS treatment.   

Consumers make decisions with their pocketbooks, so why not partner with the payers? 

Pharm Exec talks to the newly appointed leaders of the industry's most influential advocacy organizations.