After a long, contentious battle, Republicans mustered up enough votes just before Thanksgiving to approve a massive, complex bill designed to overhaul Medicare policies and provide coverage for prescription drugs. Pharmaceutical and biotech companies applauded the measure for boosting drug utilization without establishing explicit price controls. The bill also raises reimbursement for cutting-edge therapies administered in hospitals and clinics. These provisions are slated to stimulate new product development, but also set the stage for increased government scrutiny of drug prices and value.

The centerpiece of the legislation is a new prescription drug benefit for seniors, which is projected to cost at least 				

$400 billion over the next 10 years. The program begins this spring by providing seniors with Medicare-endorsed drug discount cards that could cut prescription drug costs up to 25%. In 2006, Medicare beneficiaries will be able to sign up for a new drug benefit that will cover about 75% of outpatient prescription drug costs, up to a $2250 cap. The program then will pay almost all pharmacy expenses above a $3600 "catastrophic" threshold. 	

Establishing a relatively low catastrophic level is a key feature for sponsors of new medical products. It provides assurance to sponsors testing new treatments that they will be able to gain coverage and reimbursement for future high-cost innovative products, explains Sharon Cohen, vice president at the Biotechnology Industry Organization. 	

The legislation also offers incentives for discovering therapies with innovative modes of delivery. Medicare traditionally has covered most injectables administered in hospitals, clinics, and doctors' offices, a policy that has discouraged R&D on self-administered products for the elderly. Now, companies developing new oral medicines, inhalation therapies, and other treatments using innovative delivery systems will gain coverage. A new demonstration project provides immediate reimbursement for oral cancer drugs and self-injectable therapies for rheumatoid arthritis and multiple sclerosis, and will continue for the next two years as part of a $500 million test program. The project aims to determine whether reimbursement for these products is cost-effective and increases patient access.	

Another spur for R&D may come from an expansion in Medicare benefits to provide screening for diabetes and cardiovascular disease. The program is likely to increase diagnosis and treatment of patients with these conditions, and another pilot program is offering disease management programs for seniors with certain chronic conditions.	

Although seniors still will have to pay fairly high out-of-pocket costs to obtain reimbursement for outpatient drugs, low-income beneficiaries will gain assistance in paying premiums and copays. In addition, elderly patients who enroll in managed care plans are likely to gain coverage of these costs plus the "donut hole" between the $2250 cap on regular benefits and when catastrophic coverage begins. 	

With the federal government spending $400 billion on a Medicare drug benefit, pharma companies can expect heightened Congressional and public interest in product costs and effectiveness. The legislation expects PBMs (pharmacy benefit managers) and managed care plans to establish formularies and use other management tools to extract price concessions from manufacturers.				

Controversial language in the bill prohibits Medicare officials from interfering directly in negotiations between manufacturers and PBMs. However, the Agency for Healthcare Research & Quality (AHRQ) gains resources to provide PBMs and health plans with scientific evidence and information on outcomes, comparative clinical effectiveness and appropriateness of health care services and prescription drugs. The Medicare bill provides $50 million for AHRQ to conduct or support demonstrations, evaluations, and technology assessments in this area. AHRQ will launch this program by developing a list of research priorities related to health care services and prescription drugs, with a focus on:	

underutilized or overutilized products and services

products and services that may significantly improve the prevention, treatment or cure of high-cost diseases or conditions [see sidebar:  More Evidence to Support Choices].

The Medicare legislation specifies that PBMs should base formulary decisions on scientific evidence and standards of practice, and utilize outcomes and cost-effectiveness information in making decisions on prescription drug coverage. At the same time, the bill spells out in some detail how Medicare drug plans should operate, including requirements that may hinder the ability of PBMs to negotiate rebates and discounts. Drug plans should establish P&T (pharmacy and therapeutics) committees to develop and review formularies, which must list at least two products in each therapeutic class as defined by the U.S. Pharmacopeia. Plans must provide patients access to "medically necessary" drugs and notify patients and physicians of intent to remove a drug from preferred-drug lists. There should be a system for beneficiaries to request exemptions and to appeal coverage decisions.	

The legislation also calls for plans to provide drug utilization programs, quality assurance measures to reduce medical errors, and medication therapy management programs. It remains to be seen if these requirements hamstring PBM operations so much as to discourage them from competing for Medicare business.	

Expansion in federal coverage of prescription drugs also promises to increase government monitoring of manufacturers' prices. One important, fairly technical provision revises the payment system for therapies administered in doctors' offices to shift away from reliance on average wholesale price (AWP) numbers reported by manufacturers. The aim is to curb reimbursement based on excessively inflated AWP rates for certain cancer treatments and other products that allowed unscrupulous drug marketers to market the "spread" between AWP and a much lower price actually charged the physician. The legislation reduces reimbursement for this year (2004) and then adopts a new payment formula based on average sales prices (ASP) to be calculated by manufacturers.				

To prevent future pricing scams, the legislation instructs the HHS inspector general to audit manufacturer AWP and ASP price reports regularly and compare the figures with prices available to private purchases and those reported to Medicaid. Congress specifies that manufacturers will face criminal charges for submitting false price information, a provision that aims to ensure that Medicare payments reflect the "widely available market price."	

At the same time, the legislation boosts payments to oncologists and other physicians who have opposed AWP revisions that cut rates for drugs without raising doctors' compensation for treating patients. To ensure adequate reimbursement of these practitioners, Medicare will survey physician practice expenses for drug administration, and the Medicare Payment Advisory Committee will review how payment changes affect patient access to care by oncologists and other specialties.	

In addition, government agencies will monitor and analyze the impact of expanded Medicare drug coverage from several vantage points. HHS will report on geographic variations in drug spending. The Federal Trade Commission will assess the impact of expanded mail-order pharmacy services on payments to local pharmacists. Congress' General Accounting Office will monitor any decline or expansion in employer drug benefits for retirees. 	

The Institute of Medicine (IOM) also will conduct a comprehensive study on the nature and causes of medication errors in order to improve drug safety and quality. As a follow-up to previous IOM reports on medical errors in the health care system, this study aims to help policy makers promote a "national agenda" for medication error reduction. It will develop more credible estimates of the incidence and cost of medication errors and propose a research agenda to evaluate the health and cost impacts of alternative approaches for reducing these problems. 	

Despite expanded prescription drug benefits and use of PBMs to negotiate lower drug prices, the campaign is continuing to authorize expanded reimporting of drugs from Canada and other countries. The Medicare bill includes a fairly toothless measure that permits reimporting only if HHS certifies that such activity is safe-something the agency won't do. Food and Drug Administration commissioner Mark McClellan led the administration's attack against reimporting, claiming that it would encourage distribution of counterfeit and unapproved products in the United States and thus threaten public health. But the public continues to clamor for access to cheaper Canadian drugs, and Congress is likely to revisit the issue after HHS completes a study on safety and trade issues associated with reimportation.				

Critics of the Medicare bill expect to press for further changes, and "corrections" are likely even this year. Analysts predict that the $400 billion budget for the drug benefit is likely to support the program for only a few years-not 10. A big budget shortfall will generate demand for additional payment cuts and heftier discounts on drugs and biologics. If PBMs decide not to compete for Medicare business, the federal government may end up playing a greater role in providing drug benefits. Such developments will only intensify already harsh scrutiny of drug prices and put a premium on research able to document product quality.	

Articles

View from Washington

After a long, contentious battle, Republicans mustered up enough votes just before Thanksgiving to approve a massive, complex bill designed to overhaul Medicare policies and provide coverage for prescription drugs.

Medicare Drug Coverage to Spur Pharmaceutical R&D

Pharmaceutical research and development costs are growing faster than the market.1 This trend is important, because pharmaceutical companies finance R&D from a relatively fixed percentage (10%–20%) of global revenues. As revenues stabilize and costs increase, the industry thus finds itself in a cash squeeze.2 Given the current economic environment, it is unlikely that revenues will increase to keep pace with unmanaged increases in development costs. For this reason, costs must be contained or the industry will face un-wanted program and personnel cutbacks.	

Factors limiting market growth relate to the tightening of public healthcare purse strings in developed countries and to the natural limits on voluntary consumer spending for drugs. R&D productivity continues to decline, and costs continue to rise. The following statistics only underscore this perilous trend:	

The potential for success of a new chemical entity at the beginning of Phase I is still only 10%

Nearly 90% of clinical trials are completed with significant delays.

These setbacks do not come cheaply. For a drug destined to make half a billion dollars in annual sales, a one-day delay costs about $1.3 million. Any avoidable delays to market are therefore unacceptable to anyone accountable for running a profitable business.	

The industry has certainly responded to other fiscal crises. For a quarter of a century, i.e., since the emergence of good clinical practice (GCP), we have streamlined the drug development process, aiming to increase the overall success rate of R&D, as well as to shorten the timelines. If we are to remain fiscally sound and attractive to investors, we must find additional economies.	

Figure 1. The time to develop a new drug in the clinic (duration of a program) arises from the sum of the durations of each clinical trial in the program.				

Largely, the industry has benchmarked and optimized each phase and task within the development process. At efficient companies, SOPs have transformed the actions of every clinical, data management and regulatory operations staff member into coordinated clockwork, moving clinical trials forward with Swiss precision. Protocol writing takes a few weeks. Case report form (CRF) assembly occurs within days. Computers code the data and generate tables and listings shortly after database lock.	

One might think that little room remains for improvement, believing that we can no longer reduce development timelines in any significant way. Realistically, we probably cannot systematically shrink the time required for interstudy decision-making, although some companies try. Nor can we alter the protocol-driven patient treatment and follow-up periods. Within single studies, we have compressed the duration of individual phases to the minimum. In what phase, then, can we find the potential for greater efficiency?	

The patient enrollment period is the key phase where we believe the industry has the least control. Current enrollment tactics do not respond to our need for consistent, on-time enrollment; we need a broader strategy. If we could consistently reduce the patient enrollment period in clinical trials, we would take another major leap forward in optimizing the drug development process and preserving our economic health.				

The sum of the duration of each clinical trial along the critical path, including the time related to interstudy decision-making, results in the overall time for clinical development of a new drug. We define a study along the critical path as a trial that must be completed before another time-critical study can begin. The critical path begins with the decision to launch "first-in-man" trials and ends with the decision to submit an application for marketing authorization. A clinical program may involve as many as 80 different clinical trials, however only 20% of these studies might actually be on the critical path. On the grand scale, it follows that any delay in any study on the critical path would lead to a delay in the completion of the entire development program. Since close to 90% of clinical trials experience a delay, not a single program completes on schedule. 		

Table 1.  Average Productivity Ratios by Indication between Sites in Russia, the Ukraine, and the Balkans Compared to Sites in the United States and/or Western Europe (1997-2002)	

Slow enrollment is the number one reason for the failure of clinical trials.3 Eighty-six percent of studies slip behind schedule.4 Furthermore, 60% of studies have delays of at least one month and 13% of studies are completed six months or more behind schedule. Because most clinical trials on the critical path each incur months of delays, overall development programs incur years of delays. 	

We can no longer afford to ignore this poor performance. We have developed the pernicious habit of routinely pushing back deadlines, giving ourselves the illusion that we are successfully meeting timelines while project schedules, if left unchanged, are almost never met. The practice must stop if we are to remain a financially viable industry.  	

We systematically ascribe the cause for deadline pushback to a many-fold overestimation of the patient recruitment potential by clinical investigators. The cliche "Lasagna's Law" was coined in the 1970s to describe this methodological error in enrollment estimates (see Figure 1). It is now the most popular rationale for delays in clinical projects. To compensate, many project managers think that the enrollment estimates from investigators are too optimistic by definition, and this leads to ultraconservative recruitment projections. Industry blames investigators, collectively, for the chronic delays in drug development, viewing slow enrollment as an external factor totally beyond the control of project managers; more like a quasi "act of God."								

Efficient project managers must, therefore, focus on beating Lasagna's Law at both the clinical trial and overall program levels. Better yet, project management should try to shorten the cumulative duration of patient recruitment in all studies on the critical path. Given that the enrollment period currently represents about 50% of the duration of a clinical trial, the overall development program would take 25% less time if the enrollment period shrunk by half. Reducing an eight-year clinical development program by two years translates into savings of approximately $1 billion (2 years x 365 days x $1.3 million/day), enough to finance the research and development of a new drug from inception! Faster enrollment, when achieved, would accelerate the drug development process to speeds not yet seen globally and restore the competitive edge to the industry.		

Table 2.  Percentages of FDA Audits with an OAI Outcome	

Drug developers and contract research organizations (CROs) still place most clinical trials in North America and Western Europe. The concentration of studies in these regions has led to site saturation and declining productivity. It simply will not help us to increase the number of participating sites in the traditional clinical research regions. This would inevitably lead to fewer patients enrolled per site, because recruiting additional sites often means accepting smaller centers and less experienced investigators. Worse yet, statisticians have calculated that this strategy might lead to a loss of statistical power.5 The difference in size between the smallest and largest sites would increase too, thus magnifying the risk of center effects. If the larger and more productive sites have to wait for the smaller ones to complete a block of patients, this may even nullify the advantage of having lined up a larger number of investigators.				

We propose that the only effective solution is to seek and find large sites in new territories and pool them with large sites in the traditional regions. This strategy will resolve the productivity crisis by reducing the overall duration of enrollment. 				

If investigators in the customary locations cannot deliver, where might we look for investigators with a greater enrollment potential? For the most part, we have preferred to use sites in areas where we see well-organized healthcare systems, well-trained physicians, and GCP-compliant regulatory and ethical standards. Russia, the Ukraine, and the Balkans offer the conditions for major participation in global drug development. With the efficiency concerns of today, it is time we considered the huge opportunity that this region presents.	

One hundred and fifty million inhabitants live in the Russian Federation, the largest country in Europe, both in terms of geography and population. Fifty million people reside in the Ukraine. The Balkans, including Romania (24 million), Serbia, Bulgaria, and Croatia, together represent another 50 million citizens. These countries firmly anchor themselves, culturally and economically, within the northern hemisphere, employing the same evidence-based medical systems and the same school of medical thought. They adopted GCP standards along with Western Europe and the United States, and they have a large, well-organized healthcare delivery system. Most important is the region's demonstrated ability to produce evaluable patients at a rate at least two times faster than the United States or Western Europe.	

Russia, the Ukraine, and the Balkans represent a catchment area for patient recruitment as large as North America or Western Europe. Today, the research-based pharmaceutical industry taps less than 15% of the region's clinical trial enrollment potential. It is the underutilized area of the world that can give us the answer to our patient enrollment stalemate. We have inventoried some 12,000 hospital-based sites in this region. With recruitment of just one patient per site every other week, which would not be too bold an assumption, the capacity of the region could easily reach 300,000 CRFs per year. 	

Based on about 50 international Phase II and III clinical trials, for which precise enrollment data per center and per month were available, we have derived site productivity comparisons between this region and the United States and Western Europe, in a variety of indications (see Table 1).	

The table is based on enrollment statistics provided by the sponsors or CROs monitoring the trials considered in addition to our own data. The productivity of sites was defined as the average number of patients enrolled per site per enrollment month (i.e., during the available enrollment period).	

Russia and Central and Eastern Europe (CEE) could themselves become exhausted, and therefore subjected to Lasagna's Law. We estimate that the remaining potential of Russia and CEE is 200,000 new CRFs/year. Given that an average of 4,000 subjects are needed per new chemical entity (NCE) registration, this reserve, which is available each year, represents the complete clinical development of 50 NCEs. Less than 10–12 were registered in 2002 in Europe.	

Because the average site productivity in Russia, the Ukraine, and the Balkans is at least twice as high as that in the traditional clinical research regions, it is possible to halve the enrollment period in all clinical trials on the critical path. The industry must seize the powerful economic benefits of this potential.	

Many factors contribute to the high average site productivity in the region. It has inherited a centralized healthcare system from the Soviet era, with therapeutic area hierarchies and vertical referral systems. Principal investigators, at the top of a medical specialty pyramid, can funnel patients from a large base of urban populations connected via vast and inexpensive public transportation systems. Due to a very small percentage of private medical practices, competition for patients does not exist between general practitioners and specialists in private practice or at city, regional or academic hospitals. Hospitals specialize by therapeutic area and enjoy, therefore, a semimonopolistic control of patient flow for research purposes. This allows sites to enroll previously unselected populations, whereas their Western counterparts in academia sometimes recycle the same pool of (often therapy-resistant) cases from trial to trial. 	

The cultures of Russia, the Ukraine, and the Balkans support clinical research in a number of direct and indirect ways. Since residential movement of the population is low, long-term follow-up is possible with little attrition. Patients also have lifetime medical records, segmented over various specialty hospitals and affiliated outpatient clinics. Clinical research, including pediatric studies, still enjoys a high degree of public acceptance. A well-educated population wants a high standard of care. Therefore, patients view clinical trials as a way to satisfy their desire for access to important new drugs. Excellent patient compliance arises from this motivation.				

Study staff and monitors are, invariably, physicians. The collaboration of highly educated professionals makes it possible to conduct very complex scientific protocols. This results in consistent adherence to study schedules, significantly fewer protocol deviations, and lower screen failure and dropout rates.	

Regarding the standard of healthcare, Russia, the Ukraine, and the Balkans are making a comeback in terms of Western expectations. The Russian economy is growing, and its pharmaceutical market is the fastest growing pharma segment in Europe. The per capita purchasing power in Russia (2001 per capita GDP at purchasing power parity of USD $8,300)6 is less than one half that of the Central and lower range in the European Union-comparable to that of Poland and many other Central and Eastern European countries. However, it is 30% higher than that of Brazil, more than double that of China, and more than 3.5 times the purchasing power of the Indian population. In prosperous cities, such as Moscow, St. Petersburg, Kiev, and Bucharest, but also in some secondary cities, Russian  purchasing power is closer to that of the European Union average. Hospitals in the national healthcare systems can be highly specialized by therapeutic area (e.g., oncology, cardiovascular diseases, hematopo4ic tumors in children). This guarantees the best standard of care for the available budget and a better use of limited resources for the benefit of more patients.	

Industry has tested other regions of the world for their clinical research capabilities, but several factors limit a significant contribution to the resolution of the enrollment problem. Reliable sites and countries quickly experience saturation beyond capacity. Some countries with large population bases suffer from a lack of sufficient healthcare infrastructure. Others ascribe to a non-Western medical philosophy. Finally, some regions have not yet resolved issues of quality. 				

Sponsors and CROs have been setting up studies in South Africa, Israel, Australia, and New Zealand over the past two decades. However, these countries have relatively small populations and are already inundated with clinical trials.  For example, study placements in South Africa are currently declining.	

Central and South America have been involved in clinical trials since a few HIV studies were successfully conducted there in the early 1990s. Today, the region endures profound financial turmoil. In addition, the quality of data conducted in the region has been questioned. 	

Over the last decade, countries in Central and Eastern Europe have successfully performed numerous small and medium-sized clinical trials. However, the relatively small populations of these countries limit major contributions. Poland has a sizeable citizenry of 38 million, but the other countries range from small (maximum 10 million) to very small (less than 2 million). The regulatory cost of setting up and monitoring studies in nations with a few million inhabitants presents a burden in terms of translations, language barriers for source document verification, varying regulatory systems, etc. Together, the three Baltic States, the Czech and Slovak Republics, and Hungary do not represent a greater patient extraction area than the Benelux (Belgium, the Netherlands, and Luxemburg). As a result, the number of clinical trials set up per year has reached a plateau.	

Generally, attempts at developing significant clinical research capacity in India, China, and the Far East have not yet been successful, with the exception of a few major cities such as Hong Kong and Singapore. On the African continent, little capacity exists north of South Africa, for lack of ethical and healthcare infrastructures.	

Fast enrollment, by itself, would mean little if it did not generate high-quality data. So far, the quality of clinical research in Russia, the Ukraine, and the Balkans, as well as in all of Eastern Europe, has been unaffected by the speed of patient recruitment. At the DIA 2002 meeting in Chicago, an FDA delegate presented statistics on ex-US clinical inspections it had conducted; in particular, the percentages of inspections with major findings, leading to data rejection (so-called OAI, "Official Action Indicated"), on a by-region basis (see Table 2).7				

There is a caveat about these statistics, however. The denominator, i.e., the number of inspections per region, differs greatly between regions. Whereas the FDA has conducted a few hundred inspections in Western Europe, it has inspected many fewer sites in the other listed regions. For instance, the FDA calculated Eastern European statistics based on 26 inspections, i.e., less than one-tenth in Western Europe. Nevertheless, the lack of OAIs for Eastern Europe signifies impressive data quality. Over the last 10 years, the FDA has received thousands of 1572 forms sent from this region. Most studies placed there, particularly in Russia, operate under IND regulations. National and foreign authorities are continuously inspecting clinical sites in the region. For example, in 2002 the Ukrainian Ministry of Health conducted 32 GCP inspections.	

Pharmaceutical sponsors routinely audit sites in the region because it invariably contributes a large number of top-enrolling sites. Auditors from pharmaceutical companies have published statistics evidencing the high quality of clinical data from the region.9 Auditors from global CROs, as well as freelancers, have reported similar findings.10–11	

Russia, the Ukraine, and the Balkans represent the largest concentration of highly productive sites in the world. Harnessing this potential for faster drug development requires specialized knowledge, staff, skills, and infrastructure.  				

Expertise in local regulatory affairs is critical to the success of studies in the region. Russia, the Ukraine, and the Balkans have a tradition of complex bureaucracies going back some 200 years. The region accepted ICH GCP at about the same time as the founding ICH countries adopted it. Hence, complex legislative apparatuses now exist to regulate clinical trials to the world standard. Naturally, each legislative body creates its own system for compliance. Knowledge of the systems, gained through years of experience and interaction, can greatly affect study startup timelines, compliant serious adverse event (SAE) reporting, and other key events.	

Local legal expertise is necessary to establish contracts with each of the parties involved in the conduct of a clinical trial. Hospital management and investigators call for special provisions. Patient insurance brokers speak their own professional language. Drug and clinical supplies need to be imported and cleared through customs. Biological samples require export licensing. An organization with special expertise in managing the contractual obligations inherent in the clinical trial process will ensure that each element proceeds efficiently, and without interruption to the timeline.	

Like everywhere in the world, it is of paramount importance to have a good rapport with opinion leaders. As a matter of culture, clinical research associates (CRAs) need a medical background to have sufficient educational leverage vis-Ã½is the principal investigators. Training investigators yields stable contributors of high-quality data over time, establishes and maintains rapport, and ensures adherence to ICH GCP standards. 	

It takes a critical mass of dedicated people to deploy a large study quickly and then manage highly productive sites on a continuous basis. If a trial has 100 sites, each enrolling at a rate of four patients per month, sheer manpower and intense oversight is needed to maintain the necessary level of control. Monitoring will certainly be much more labor-intensive due to high patient enrollment numbers, the necessity to coach investigators, the travel time, an abundance of source records, and very detailed clinical narratives.	

A centralized drug storage facility offers a huge advantage in Russia, the Ukraine, and the Balkans. Although costly to set up and maintain, it is nevertheless indispensable for ensuring the availability of sizeable stocks, on the right side of the import barriers, with environmental controls in place (temperatures can swing from +40Â°C to -50Â°C). The ability to supply high-enrolling sites with study drug quickly, and across eleven time zones, mitigates the costs of such a system. 	

Finally, everyone who has ever placed studies in the region says that the most challenging issues relate to the logistics of conducting clinical trials. Indeed, this region is a paradise for problem-solvers. Those who can systematically manage the innumerable practicalities of efficiently running clinical research in Russia, the Ukraine, and the Balkans will be able to elicit their fullest enrollment potential.	

Feature Article

Pharmaceutical research and development costs are growing faster than the market.1 This trend is important, because pharmaceutical companies finance R&D from a relatively fixed percentage (10%?20%) of global revenues.

Speeding the Critical Path

The process of conducting clinical trials with plasma-derived products is essentially similar to that for any pharmaceutical product. However, trials with these products do present some different challenges in terms of trial design, patient recruitment, and clinical trial supplies. This article addresses these issues and describes the indications for use of plasma-derived products and the production process. 	

Before 1960, plasma was the only agent generally available for the treatment of some genetically inherited disorders such as hemophilia. Passive protection against a number of infectious diseases was achieved by injecting animal serum containing artificially induced antibodies. Now, human plasma-derived products are widely available for the treatment of a variety of conditions ranging from congenital deficiencies of coagulation factors to primary immunodeficiency and passive immunization. The plasma-derived products available generally fall into three categories: coagulation factors, immunoglobulins, and human albumin solutions, details of which are given in Table 1.1

Figure 1. Plasma fractionation pathways. (Modified from "Plasma, plasma products and indications for their use," in ABC of Transfusion, 3rd ed., 1998, Ch. 8, 40-44, by H. Cohen, P.B.A. Kernoff, B.B.T. Colvin. Reproduced by kind permission of BMJ Books.)				

1. Coagulation factor concentrates. Coagulation factor concentrates are used predominantly to treat congenital coagulation factor deficiencies. These are rare disorders, the most well-known of these being deficiencies of factor VIII (hemophilia A) and factor IX (hemophilia B), although the most commonly inherited bleeding disorder is von Willebrand disease.2 	

2. Immunoglobulins. Nonspecific (normal) immunoglobulin contains antibodies to all the micro-organisms prevalent in the donor population. Intravenous immunoglobulin is used mainly to treat patients with primary immunodeficiency syndromes (PID), including congenital hypogammaglobulinemia, common variable and severe combined immunodeficiencies, secondary hypogammaglobulinemia in patients with chronic lymphocytic leukemia, and multiple myeloma with recurrent infections. Other licensed indications for nonspecific immunoglobulins are idiopathic thrombocytopenic purpura (ITP), allogeneic bone marrow transplantation, Kawasaki Disease, and Guillain-Barre syndrome. Nonspecific immunoglobulins have been used outside the licensed indications to treat other autoimmune diseases, e.g., multiple sclerosis.	

Specific immunoglobulins are obtained from donors whose plasma contains selected high-titre IgG antibodies against a specific antigen, as a result of either previous infection or active immunization. Preparations are available for use in passive prophylaxis of varicella-zoster, tetanus, hepatitis B, and rabies. Anti-RhD immunoglobulin is used in the prevention of hemolytic disease of the newborn.	

Table 1.  Plasma-derived products; indications for use	

3. Human albumin solutions. Human albumin solutions were developed in the United States during World War II to provide an alternative to blood or dried plasma for resuscitating military casualties.3 Since the availability of these early preparations, the purity of human albumin solutions is much improved, with a low incidence of adverse reactions. Human albumin solutions are currently used for the clinical management of: hypovolemic shock associated with blood loss, trauma, and surgical procedures; the clinical management of burn injuries; and fluid replacement regimens in therapeutic plasma exchange.	

Fractionation of plasma into its different component parts was first developed by Edwin Cohn in 1944, and the modern manufacturing methods of plasma-derived products are based on his pioneering work. However, manufacturers continue to introduce new purification or viral inactivation/removal steps to further improve product safety. The plasma fractionation pathways are given in Figure 1.1				

By virtue of the fact that plasma-derived products emanate from a substance taken from human beings, i.e., plasma, there is a risk of transmission of blood-borne viruses. In this context, there are two main types of viruses; lipid-enveloped viruses, e.g., human immunodeficiency virus (HIV) and hepatitis C virus (HCV), and nonlipid-enveloped viruses, e.g., hepatitis A virus (HAV) and parvovirus B19. Lipid-enveloped viruses are relatively easy to inactivate, whereas inactivation of nonlipid-enveloped viruses is more difficult. During the early 1980s, coagulation factor concentrates caused widespread transmission of HIV and non-A, non-B hepatitis (now recognized as mainly hepatitis C) with the result that manufacturers introduced steps to inactivate or remove these and other blood-borne viruses. Further outbreaks of HAV transmission in hemophiliacs in the early 1990s led to the Committee for Proprietary Medicinal Products (CPMP) to recommend that the manufacturing process should include a viral inactivation/removal step that is effective against nonlipid-enveloped viruses.4 	

Manufacturers now take measures to ensure minimum contamination of the starting plasma and to maximize elimination of blood-borne viruses and other infectious agents during the production process. In order to ensure minimum contamination of the starting plasma, manufacturers will ensure rigorous screening of donors and employ stringent tests for the presence of blood-borne viruses from donation and throughout the production process. During the manufacturing process, the plasma and process intermediates will be subjected to a variety of viral inactivation and removal procedures. Examples of these procedures include solvent/detergent treatment, which inactivates lipid-enveloped viruses, and viral filtration, which if the pore size of the filter is 15nm or less can remove small nonlipid-enveloped viruses such as parvovirus B19.	

Given the modern manufacturing methods available, plasma-derived products have enjoyed an excellent safety record in recent years. However, there is still a risk that current viral inactivation/removal techniques may fail to eliminate all blood-borne viruses. Concern has arisen more recently that variant Creutzfeldt-Jakob disease (vCJD) may be transmitted by plasma-derived products. Abnormal prion proteins are thought to be the cause of vCJD, and although research appears promising, no test for the abnormal prion proteins is yet available. Importantly, however, to date there is no evidence of transmission of vCJD by plasma-derived products. Research suggests that the agent causing vCJD is unlikely to be carried through into the final product at levels capable of causing the disease. Although research for a test for the abnormal prion proteins appears encouraging, the availability of such a test does raise concern on the effect of donor numbers, as individuals may decline to donate fearing that the test suggests they may have a fatal disease, with a very long incubation period.5		

Table 2.  Adopted and Draft Guidelines for the Clinical Investigation of Plasma-derived Products as published by the CPMP (August 2003)	

While one of the aims of the production process for plasma-derived products must be to inactivate or remove viruses, it is also essential to ensure that the biological function of the plasma protein is retained. Any change in a manufacturing procedure may alter the structure of the plasma protein and its activity, with the potential for patients to mount an immune response to the product they are being treated with.	

Within the hemophilia population, the occurrence of an antibody against, for example, factor VIII, a so-called "inhibitor," is the most important treatment complication. Inhibitors occur in up to 30% of patients with severe hemophilia A, usually within the first 100 exposure days. Two inhibitor "outbreaks" occurred in the early 1990s in previously tolerant patients who had been treated for a number of years following exposure to plasma-derived products subjected to a modified virus inactivation method. Thus, the incidence of inhibitor formation may be affected by the specific product used for treatment and its potential to result in alteration of factor VIII molecules, "neoantigens."4 In addition to concern that the protein structure might be altered during the production process, manufacturers are also worried about the presence of trace proteins in products, because these might cause immunological reactions in patients. Therefore, manufacturers need to ensure that the biological function of the plasma protein is retained during the production process, and thereby the safety of the product is assured with respect to immunogenicity.	

Collection of data addressing efficacy and safety with respect to immunogenicity, transmission of blood-borne viruses, and other adverse events is therefore essential in the design of clinical trials with plasma-derived products. These matters are equally important whether a clinical trial is being conducted on a newly developed product or on an existing product that has undergone a significant change in the manufacturing process.	

Table 3.  Number of patients to be studied for "new product" as recommended in the CPMP Notes for Guidance 	

The CPMP has published several Notes for Guidance on the clinical investigation of plasma-derived products. Draft Notes for Guidance are first discussed within the Blood Products Working Group and then released for consultation by the wider community of stakeholders before being finalized and adopted by the CPMP. Adopted guidelines are subject to regular revision.				

The Notes for Guidance describe the information to be documented to demonstrate efficacy and safety when an application for marketing authorization is made. Typically, for a pharmaceutical product, the application for a marketing authorization would include data from several clinical trials in a Phase I–III program. The Notes for Guidance, however, describe a smaller number of studies on which data is to be submitted, which do not necessarily conform to a typical Phase I–III program.	

Each of the Notes for Guidance is divided into two sections,  "new products" and "modified products." The "new products" section relates to products not in a manufacturer's current portfolio for which a company is applying for marketing authorization. The "modified products" section relates to previously authorized products where a significant change in the manufacturing process has been made (e.g., additional viral inactivation/removal steps or new purification procedures). However, there is little difference in the clinical trials recommended for  "new" and "modified" products. Details of the adopted and draft CPMP guidelines are given in Table 2.6 	

As previously stated, it is of paramount importance when designing clinical trials of plasma-derived products to collect data addressing the efficacy and safety with respect to immunogenicity, blood-borne virus transmission, and adverse events. These aspects are reflected in the Notes for Guidance published by the CPMP.	

Interestingly, virtually all the clinical trials detailed in the Notes for Guidance are open and uncontrolled in design. Each Note for Guidance gives recommendations for assessment of the pharmacokinetics, efficacy, safety, and viral safety of the plasma-derived product and indication to be studied. For assessment of efficacy, the Notes for Guidance will typically recommend the provision of pharmacokinetic (PK) data including in-vivo half life, area under the curve (AUC), and clearance, in addition to other measurements, e.g., consumption of product and clinical response to treatment. Assessment of safety will include monitoring of adverse events and immunogenicity. Because of the rigorous selection and screening of donors and the use of viral inactivation/removal methods during the production process, the CPMP place less emphasis on monitoring viral infection markers than during the mid- to late-1990s. 	

However, the Notes for Guidance recommend that a pretreatment serum sample be taken from each patient included in the clinical trials and stored at –70Â°C for possible future testing. Manufacturers must also provide information with the marketing authorization submission on the selection and testing of the source material, the testing of the capacity of the production process to remove or inactivate viruses, and the testing of the product at appropriate stages of production.	

With regard to the number of patients to be recruited, the Notes for Guidance clearly state the minimum number of patients to be studied and submitted for marketing authorization. Examples for some of the products and indications are given in Table 3.4, 7-8 The sample sizes are small, which is a reflection that patients suffering from the conditions to be studied are rare and therefore difficult to recruit.	

For plasma-derived products where there are no CPMP guidelines available, or for indications not yet generally acceptable to the regulatory authorities, a more conventional program of statistically powered clinical trials will need to be conducted and submitted for marketing authorization.	

The US Food and Drug Administration (FDA) does not publish guidelines in quite the same way as the CPMP, although it does offer guidance to individual manufacturers with regard to the clinical trial requirements for plasma-derived products. Although the trial design and sample size requirements may differ between FDA and the CPMP, the primary endpoints would be similar for the products and indications to be studied. An example would be for a clinical trial of intravenous immunoglobulins in primary immunodeficiency syndromes, both FDA and the CPMP would require clinical data on the infection rate, the number of adverse events, and the pharmacokinetics of the product.	

Many plasma-derived products are used to treat patients with relatively rare genetically inherited disorders, and the target patient populations are therefore often small. Within the United Kingdom, there are approximately 5,000 individuals registered with hemophilia A and 1,100 registered with hemophilia B.9 Worldwide, there are estimated to be more than half a million people with hemophilia (prevalence varying from 105 to 160 per million of the male population).2 If one looks at the number of patients affected with primary immunodeficiency syndromes, there are approximately 5,000 affected patients within the United Kingdom.10 Given that the patient populations are often small, recruitment into a clinical trial of a plasma-derived product in one of these rare disorders can be a slow process. It is therefore usual to plan trials as multicenter studies, even when the sample size is small, e.g., 12 patients.								

Treatment of patients is another consideration. For example, in the case of patients with hemophilia, the bleeds that these patients suffer will vary in frequency according to the severity of their disease. Bleeds can be treated either as they occur (on demand) or treatment can be given regularly to prevent bleeds occurring (prophylaxis). With treatment and proper care, people with hemophilia can live perfectly healthy lives. Without treatment, hemophilia can cause crippling pain, severe joint damage, and early death. However, only 25% of people with hemophilia in the world receive adequate treatment.11 In developed countries, where access to treatment is good, many of the patients targeted are treated continuously for their condition and may not be willing to switch from their current product to a different product undergoing clinical trial. This may not be such an issue if the product under trial offers a significant advantage over their current treatment. An example might be that the new product is of higher purity and improved safety. Another example might be if the study is conducted in a country where supply of product is limited and patients are offered treatment prophylactically under the trial protocol when their current treatment regimen may be on demand to treat major bleeds. Similar considerations would need to be given to patients recruited for other rare disorders, for example primary immunodeficiency syndromes. Access to product on completion of the clinical trial must be discussed with the clinicians at the initiation stage. It may be that product is offered to patients under the  "particular patient" scheme, until the product receives a marketing authorization. Due to the fact that the CPMP guidelines describe open, uncontrolled trials, continuation of product is relatively straightforward, the most important issue being that sufficient product must be ensured.	

By consenting to participate in a trial, patients may be asked to switch products, undergo lengthy pharmacokinetic assessments, have more frequent hospital visits, have more blood samples taken, and have to complete trial documentation, e.g., diary cards. In addition, due to the rarity of some of the conditions to be studied, some patients may have already participated in several clinical trials. Therefore, one is often relying on the goodwill and altruism of patients to participate to a greater extent than in most other trials. 	

Clinical trial supplies for plasma-derived products present some challenges, but in essence no more than for any other pharmaceutical product. Supplies must be planned well in advance, packed, and labelled appropriately and drug accountability records kept. The CPMP guidelines state that data from the use of three batches of product needs to be submitted, and this needs to be planned with the production team at the study design stage. Plasma-derived products generally have a production lead time of about five months. This lead-time is made up of a 60-day inventory hold between donation and the start of production and 12 to 14 weeks in the production process. This production lead-time therefore needs to be taken into account when planning a clinical trial. Other issues that need to be addressed during the planning stages are:				

Volume of product required. Products are dosed on a dose/kg basis, and therefore requirements at the outset can only be estimated. Moreover, some patients may need to use more product than anticipated; for example, hemophiliac patients will suffer bleeds and-depending on the severity of the bleed-may use much more product than allowed for. Accordingly, a rigid check of product usage must be kept at the monitoring visits.

Volume of product available. Due to the fact that there is always the possibility that a batch may fail during the production process, for example if the batch is virally contaminated, it is wise to build up a buffer stock of product before commencing a trial to ensure continuity of supplies for trial patients.

Batch traceability. It is essential to ensure that each batch that is given to a patient can be traced, because of the potential for viral contamination.

Essentially, the process of conducting clinical trials on plasma-derived products is the same as for any other pharmaceutical product, although some different challenges do present themselves in terms of clinical trial design, patient recruitment, and supply of product. As with all clinical trial programs, the data must satisfy the regulatory authority to which a marketing authorization is being made with respect to efficacy and safety of the product. 	

The major differences between plasma-derived and other pharmaceutical products are in two areas. First, by virtue of the fact that plasma-derived products are extracted from a substance taken from human beings, there is a risk of viral transmission. Secondly, because the plasma is subjected during the production process to stringent purification methods, there is a risk that the biological characteristics and activity of the component proteins may be altered. For these reasons it is essential to ensure that concerns with regard to transmission of blood-borne viruses, immunogenicity, and other adverse events, as well as efficacy of the product, are addressed when designing clinical trials for them. As a result, clinical trials on plasma-derived products pose their own particular issues, and each day brings a new challenge.	

1. H. Cohen, P.B.A. Kernoff, B.B.T. Colvin, "Plasma, plasma products and indications for their use," in ABC of Transfusion, 3rd ed.(1998, Ch. 8, 1998, pp. 40–44).				

2. P.H.B Bolton-Maggs and K.J. Pasi, "Haemophilias A and B," The Lancet, Vol. 361, 24 May, 2003.	

3. B.L. McClelland, "Human albumin solution" in ABC of Transfusion, 3rd ed. (1998, Ch. 9, pp. 45–48).	

4. Note for Guidance on the Clinical Investigation of Human Plasma Derived Factor VIII and IX Products.  CPMP/BPWG/198/95 rev.1.	

5. B.L. Evatt, A. Farrugia, A.D. Shapiro, J.T. Wilde.  Haemophilia 2002: Emerging Risks of Treatment.  Haemophilia 2002; 8: 221–29.	

6. The European Agency for the Evaluation of Medicinal Products:  published on the Web site 

7. Note for Guidance on the Clinical Investigation of Human Normal Immunoglobulin for Intravenous Administration (IVIg). CPMP/BPWG/388/95 rev.1.	

8. Note for Guidance on the Clinical Investigation of Human Normal Immunoglobulin for Subcutaneous and Intramuscular Use.  EMEA/CPMP/BPWG/283/00.	

9. UK Haemophilia Centre Doctors' organisation. Report on the Annual Returns for 1999. UKHCDO, 2002.	

10. Information from the PiA (Primary Immunodeficiency Association).	

11. World Federation of Hemophilia: published on the Web site 

Kate Gillanders is clinical research manager, Bio Products Laboratory, Dagger Lane, Elstree, Herts WD6 3BX, United Kingdom, +(44) 20 8258 2562, fax +(44) 20 8258 2611, email: 

The process of conducting clinical trials with plasma-derived products is essentially similar to that for any pharmaceutical product. However, trials with these products do present some different challenges in terms of trial design, patient recruitment, and clinical trial supplies.

Conducting Clinical Trials with Plasma-derived Products

It may be known as "the old continent," but Europe sure as hell comes up with plenty of new rules. And as another old year blends into a new year, the international clinical trials community can look forward to plenty of regulatory novelty from Brussels.	

For instance, anyone manufacturing investigational products in Europe-or doing trials with them there-has just a couple of months now to modify their operating systems if they want to avoid trouble with the new European Union rules for investigational medicines.1	

EU member states are to bring these rules into force by 30 April 2004 at the latest. The new rules represent yet another small step in the EU's long and sometimes painful journey towards a harmonized framework for medicines and clinical trials. The foot soldiers of the clinical trials community might also be excused for feeling occasionally bruised by this relentless onward march.	

This new milestone along the route is an update of good manufacturing practice (GMP), but with a particular focus on the new EU obligations on clinical trials,2 which provided for detailed guidance to be drawn up on the evaluation of investigational medicines for human use within the EU.	

So, the EU has extended and adapted its existing provisions on GMP3 to cover GMP of investigational products, and most of the changes relate directly to this new area of regulation. The new rules also tighten up on GMP for authorized products, too (see sidebar).	

But of most direct interest to readers of this publication, the new rules contain provisions explicitly "in order to protect the human beings involved in clinical trials." When investigational products are imported from outside the EU, "the importer shall ensure that the products have been manufactured in accordance with standards which are at least equivalent" to EU standards, and that the products "have been manufactured by manufacturers duly authorized to do so." In particular, "An importer of investigational medicinal products shall ensure that such products have been manufactured by a manufacturer notified to the competent authorities and accepted by them for that purpose."	

For investigational products, the manufacturer is to ensure that all manufacturing operations are carried out in accordance with the information provided by the sponsor, in line with the requirements of the 2001 Clinical Trials Directive. And he or she must regularly review his or her manufacturing methods in the light of scientific and technical progress and the development of the investigational product.

The emphasis on training in the new rules, particularly on "the theory and application of the concept of quality assurance and good manufacturing practice," makes specific reference to "the particular requirements for the manufacture of investigational medicinal products."	

To make sure the entire process can be effectively inspected, established procedures for general manufacturing operations and conditions are going to have to be kept available, together with specific documents for the manufacture of each batch. Those documents will provide the history of the manufacture of each batch and of any changes introduced during the development of an investigational medicinal product.	

The rules on batch documentation are more demanding for investigational products than for authorized products. Batch documentation for authorized medicines will normally have to be retained for at least one year after the expiration date of the relevant batches, but in some circumstances this obligation may run to as much as five years. But for investigational products, "the batch documentation shall be retained for at least five years after the completion or formal discontinuation of the last clinical trial in which the batch was used." The sponsor (or, if different, the marketing authorization holder) will be responsible for ensuring that records are retained as required for marketing authorization.	

Production must be in line with pre-established instructions and procedures, with adequate in-process controls. All process deviations and product defects must be documented and thoroughly investigated, and appropriate technical or organizational measures shall be taken to avoid cross-contamination and mix-ups. In the case of investigational products, "particular attention shall be paid to the handling of products during and after any blinding operation."				

The manufacturing process for investigational products "shall be validated in its entirety in so far as is appropriate, taking into account the stage of product development." At least the critical process steps, such as sterilization, must be validated. And all steps in the design and development of the manufacturing process must be fully documented.	

A quality control system, under the authority of a qualified person independent of production, and with appropriately staffed and equipped testing laboratories, must be established. If a contract laboratory is used for investigational products, the sponsor must ensure that the contract laboratory complies with EU rules.	

During the final control of the finished product before its release for sale or distribution or for use in clinical trials, the quality control system shall take into account, in addition to analytical results, essential information such as the production conditions, the results of in-process controls, the examination of the manufacturing documents, and the conformity of the product to its specifications, including the final finished pack. 	

Samples of each batch of finished medicinal product shall be retained for at least one year after the expiration date. For an investigational medicinal product, sufficient samples of each batch of bulk-formulated product and of key packaging components used for each finished product batch shall be retained for at least two years after completion or formal discontinuation of the last clinical trial in which the batch was used, whichever period is longer.	

And there are specific provisions on the labelling of investigational products. "Labelling shall ensure protection of the subject and traceability, to enable identification of the product and trial, and to facilitate proper use of the investigational medicinal product."	

Elaborate arrangements for product recall are required. The manufacturer of investigational products must, in cooperation with the sponsor, "implement a system for recording and reviewing complaints together with an effective system for recalling promptly and at any time investigational medicinal products which have already entered the distribution network. The manufacturer shall record and investigate any complaint concerning a defect and shall inform the competent authority of any defect that could result in a recall or abnormal restriction on supply." All trial sites must be identified and, in so far as is possible, the countries of destination must be indicated. And if the investigational product already has a marketing authorization, the manufacturer, in cooperation with the sponsor, must inform the marketing authorization holder of any defect that could be related to the authorized product.	

The sponsor must also implement a procedure for the rapid unblinding of blinded products-where this is necessary for a prompt recall-but the procedure must disclose the identity of the blinded product only in so far as is necessary.	

While the detailed regulations gradually fall into place on the more technical aspects of clinical trials-the tactics, as it were, of regulation-the European Union is also still deep in the throes of creating a new strategic framework for its pharmaceutical legislation, covering everything from the organization of the European Agency for the Evaluation of Medicinal Products (EMEA) to the handling of pharmacovigilance and the protection of intellectual property. This is a slow-moving process, which has been underway since 2000. This column last offered an update in the middle of last year (ACT, July 2003), and the exercise is still far from completed.				

However, as 2003 drew to a close, at least one aspect of this huge debate was drawing attention to the significance of clinical trials. Much of the discussion in Brussels polarized around a high-profile dispute between the innovative pharmaceutical industry and generic manufacturers over access to data. 	

Regulatory data protection-an innovator's right to prevent copying of the information generated to support an application for marketing authorization-is "vital to stimulate research for the benefit of patients," insisted the European Federation of Pharmaceutical Industries and Associations (EFPIA), as EU legislators argued over how long an innovator should be able to keep a generic copier off its back.	

And the European biotechnology industry association, EuropaBio, warned that any reduction in intellectual property protection in Europe would have a damaging effect on the European pharmaceutical industry as a whole. According to its secretary general, Hugo Schepens, intellectual property protection is "the lynchpin" of the current debate on pharmaceutical regulation-and the calls for cuts in protection coming from some parts of the EU legislative machinery must be resisted. "We can't accept that protection is cut back," he said.	

What most of the debate comes down to is at what point generic firms should be entitled to make reference to an innovator's clinical trials data to support a marketing authorization application for a copy product. Hawks among the innovator camp want a blanket 10-year period of protection for such data (with the possibility of extensions to 11 years where new indications are found). Generic firms should be required to carry out adequate safety and efficacy testing themselves-particularly for biological or biotechnology-derived products. Preclinical tests and clinical trials are essential to demonstrate product safety and efficacy, EFPIA says, since "Biological medicinal products are not the same as chemical medicinal products and cannot be treated the same. Since they are very complex entities, even small differences in their physicochemical nature or production process can result in major differences in their biological properties...such differences could result in a loss of efficacy and/or emergence of clinical safety issues and therefore become a threat to public health."	

Meanwhile, the hawks among the copyist camp say that three years is more than enough time for innovators to make profits out of exclusivity over such data. The European Generic Medicines Association rejects the innovative industry's calls for "restrictive changes to the definitions of a generic medicine and a bio-similar medicine, restrictions on the manufacturing of generic medicines in contradiction to current practice in international patent law," and "special protection periods for products." And it accuses big pharmaceutical firms of pushing for additional amendments "which would further increase the period of time generics must wait before authorization."	

The end of 2004 should see a conclusion to this debate-and to the debates on the other issues in this major overhaul of the EU pharmaceutical framework. And you know what that means: more new rules! 	

1. Commission Directive 2003/94/EC laying down the principles and guidelines of Good Manufacturing Practice in respect of medicinal products for human use and investigational medicinal products for human use	

2. Directive 2001/20/EC of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use.	

View from Brussels

It may be known as "the old continent," but Europe sure as hell comes up with plenty of new rules.

Need More EU Rules? Here's Another One

Raymond L. Hecker, M.B.A., B.S.A.E., is vice president of business development at Franek Technologies, Inc. and author/instructor of the Power Protection of Mission Critical Medical and Laboratory Equipment course, offered at UC Irvines Learning Center on Jan. 24, 2004.

Was the Northeast blackout a told you so about overconfidence in our power?


It was actually the power shortages and blackouts in California during the first half of 2001 that was the primary reason for developing this course. Political de-regulation and industry management in the United States were and still are the reason for the shortfall of power generation and distribution.

Short of grid collapses, what are some other causes of power fluctuations?


The power problems that we face  are based upon an aging power generation system, insufficient power distribution, digital equipment running on a power distribution system that was designed for analog devices, (which induces large current swings in the power system), old building wiring that becomes overloaded with energy-inefficient devices, and more users in a concentrated area.

The main power quality issues for risk facilities and laboratory managers include switched transients, interrupt transients, harmonic distortion, electromagnetic and radio frequency interference (EMI/RFI) noise, variable frequency, under- and over-voltage, and sags and surges of voltage.

Which one is usually the culprit  lightning, a downed power grid, or a labs HVAC system turning on?


Lightning and downed power lines are a primary cause of power surges in the power distribution grid, and sets up current and voltage surges like a tidal wave that must be redirected or the distribution system will become unstable. Events like these or the failure of a sub-station or switching yard caused the cascading and catastrophic failure in the California grid in 2001 and the power outages in 2003. 

Power disturbance culprits like a HVAC system turning on and/or more digital equipment being used in a facility are considered local power distribution issues that adversely affect the lab. One of the most prevalent power-disturbing devices in the lab is the centrifuge.

How could this affect my labs power supply?


The amount of current demanded by the consumers determines the amount of power that is generated and made available to meet the demand. In a power flood the power is redirected to ground or wasted as heat until the generating capacity is reduced and reset. If too little power is available a drought occurs and the electrical load must be shed. Users, such as labs and other businesses, are knocked off of the power system. Brown-out conditions are avoided as serious damage can result to all users and generating stations. Rolling blackouts are generally employed by the utilities to shed major load variances.

Once the power is released to the distribution segments of the delivery channel, the power becomes adulterated. None of us would drink stream water without some preparation for potability. The electric power that is generally available to the lab is equivalent to stream water that has not been filtered, deionized or decontaminated.

How much damage could a power loss cause to a typical clinical and/or research lab?


An interrupt in power or the induced failure of a component or a device in an instrumentation system due to poor power quality generally has a price tag starting at $2,000 to $4,000 per incident. An incidents time duration can be as low as 9 milliseconds or may go on for many minutes or hours. In our experience with a typical instrumentation system, the annual cost for not using appropriately corrected power of instrumentation grade quality approaches $25,000 per year for each instrument system that is subjected to electrical power quality issues. Switching transients are the most frequent cause of surges and spikes to any electrical device, and occur approximately 50,000 times more frequently than a power outage.

Power interruptions and perturbations cause losses of over $5 billion per year to key medical equipment, information systems, and laboratory automation systems that rely directly on utility power.

Should I be more concerned if Im in a old building?


New buildings or major power distribution modifications to buildings since 1997 have adapted to larger sizing of electrical circuit conductors and the wiring of buildings for secure power circuits (orange-colored receptacles). Special digital capable circuits are designed to accommodate the larger currents that are generated by digital computers and other computer-controlled devices.

Building circuits that are not designed for digital loads have been designed for our traditional analog devices and the normal AC wave [perfect power is represented in a sine wave; power problems look like irregular waves] that powers those devices. Analog types of circuits tend to overheat and become electrical hazards when digital or switching currents are applied to them. The immediate result is voltage sag and/or under voltage that can corrupt computer data as well as literally burn up electrical devices. Any building or circuit that is not designed for digital loading will be problematic unless power regeneration devices are incorporated. 

Whats required to be 21 CFR 11 compliant, power-wise?


Both the FDA and HHS require in their guidance documents that the source of electrical power meet the manufacturers specifications for input power quality. Laboratories cannot meet those specifications unless the utility power has been reconditioned and synthesized into the desired AC voltage waveform that is within frequency limits originally generated by the utility.

Some labs have their electrical equipment plugged into surge protectors. Is that enough to be compliant?


No. In fact most laboratories do not provide surge protection devices for their instrumentation. Surge protection is only one aspect of the nearly dozen power quality issues required to condition and synthesize power into an acceptable energy resource for instrumentation and bioinformatics applications. A Category III-3 (or instrumentation-grade) laboratory protection system (LPS) device is an uninterrupted power source (UPS) of the highest grade, that is both utility voltage and frequency independent. 

LPS devices are also utilized as frequency converters for some international applications. LPS devices convert utility AC power into DC power (similar to a distillation process) and then regenerates the DC power into a computer-controlled synthesized pure fidelity AC wave form that is rigorously controlled for voltage, current and frequency.

Not all cars can use a low grade of gasoline; racing cars require special octanes. Adding a Category I or II UPS to a Category III instrumentation application will most likely damage the instrument system and void the manufacturers warranty, especially those instrument systems that incorporate lasers in their design.

How much would it cost an average lab to safeguard their electronics?


The cost of adding certified Category III-3 instrumentation power protection LPS to a laboratory is essentially free. The general cost of extended warranty, re-agents, consumables, controls, calibrators and primers generally approaches 25% or more of the base cost of the instrumentation system. Adding an appropriate LPS to the instrumentation eliminates any lost research time, retesting, recalibration and instrumentation damage and repairs associated with using raw utility power. The cost-to-benefit ratio of adding LPS protection to the lab per year approaches a savings of approximately 5:1 to 15:1.

In terms of upfront cash outlay, a LPS device generally costs less than 3-4% of the initial instrument acquisition cost and much less than 1% per year in operational cost. The net result is that there is no additional cost to the lab for adding LPS protection, as compared to operating without protection.

Are there any maintenance issues with a LPS to be aware of? Or do managers never have to deal with power-supply issues again once they have an LPS? 


As with any product, the LPS device should be periodically monitored for overall performance and utilization. Fans should be checked annually for any build up for lint and dust, as you would do for your computer system. Batteries last between 4--6 years. 

Once a LPS unit is installed, though, the labs power quality issues are eliminated.

Latebreakers

Power source Raymond Hecker explains what's required to be 21 CFR 11 compliant, power-wise.

Applied Clinical Trials-01-01-2004

Medicare Drug Coverage to Spur Pharmaceutical R&D

Speeding the Critical Path

Conducting Clinical Trials with Plasma-derived Products

Need More EU Rules? Here's Another One

What Does a Blackout Have to Do with Being 21 CFR Part 11 Compliant?