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Gaps, Tensions, and Conflicts in the FDA Approval Process: Implications for Clinical Practice

Posted in Bio Instrumentation in Experimental Life Sciences Research, Ecosystems & Industrial Concentration in the Medical Device Sector, FDA Regulatory Affairs, Medical Devices R&D and Inventions, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, tagged Dalkon Shield, FDA, Food and Drug Administration, Kessler, Medical device, Medical Devices R&D and Inventions, Premarket approval, Richard A. Deyo, University of Washington on July 31, 2012| 3 Comments »

Gaps, Tensions, and Conflicts in the FDA Approval Process: Implications for Clinical Practice

Reporter: Aviva Lev-Ari, PhD, RN

FDA 501(k) Approval Process

Posted by DCNGA » Wed Nov 03, 2010 4:24 pm

Medical Devices: Gaps, Tensions, and Conflicts in the FDA Approval Process: Medical Devices

Author: Richard A. Deyo, MD, MPH, Departments of Medicine and Health Services and the Center for Cost and Outcomes Research, University of Washington, Seattle

The FDA’s approach to approving medical devices differs substantially from the approach to drugs, being in some ways both more complex and less stringent.[13] The FDA’s authority over devices dates only to 1976. Device legislation was a response, in part, to public outcry over some well-publicized device failures. The most prominent was the Dalkon Shield—an intrauterine contraceptive device associated with serious infections.[14] In contrast, the FDA’s authority over drugs dates to 1938, although it existed in weaker form starting in 1906.[15]

With few exceptions, given the timing of the FDA’s authority, devices introduced before 1976 were never required to undergo rigorous evaluation of safety and efficacy. With the huge volume of “things” that suddenly fell under its purview, the FDA had to prioritize its resources and efforts.

One way of prioritizing was to focus first on safety. Evaluation of effectiveness, in many cases, was reduced to engineering performance: does the device hold up under its intended uses, does it deliver an electric current as advertised? The potential benefits for relieving pain, improving function, or ameliorating disease did not generally have to be demonstrated.

Another way of prioritizing was to assign categories of risk associated with the devices. Rubber gloves seemed less risky than cardiac pacemakers, for example. So the agency assigned devices to 1 of 3 levels of scrutiny. Class I devices have low risk; oversight, performed mainly by industry itself, is to maintain high manufacturing quality standards, assure proper labeling, and prevent adulteration. Latex gloves are an example.

At the other extreme, class III devices are the highest risk. These include many implantable devices, things that are life-supporting, and diagnostic and treatment devices that pose substantial risk. Artificial heart valves and electrical catheters for ablating arrhythmogenic foci in the heart are examples. This class also includes any new technology that the FDA does not recognize or understand. New components or materials, for example, may suggest to FDA that it should perform a more formal evaluation. In general, these devices require a “premarket approval,” including data on performance in people (not just animals), extensive safety information, and extensive data on effectiveness. This evaluation comes closest to that required of drugs. In fact, Dr. Kessler says, these applications “look a lot like a drug applications: big stacks of paper. They almost always require clinical data—almost always. And they often require randomized trials. Not always, but often” (L. Kessler, personal communication). These devices are often expensive and sometimes controversial because of their costs.

Class II devices are perhaps the most interesting. They comprise an intermediate group, generally requiring only performance standards. Examples would be biopsy forceps, surgical lasers, and some hip prostheses. The performance standards focus on the engineering characteristics of the device: does it deliver an electrical stimulus if it claims to, and is it in a safe range? Is it made of noncorrosive materials? Most of these devices get approved by the “510(k)” mechanism. The 510(k) approval requires demonstrating “substantial equivalence” to a device marketed before 1976. “And,” says Kessler, “the products that have been pushed through 510(k) are astonishing” (L. Kessler, personal communication).

Kessler points out, “For the first 5 to 10 years after 1976, this approach made sense. But in 2001, 25 years after the Medical Device Amendment, does it make sense? There was a lot of stuff on the market that wasn’t necessarily great in 1975—why would you put it back on the market now?” (L. Kessler, personal communication). The new device need not prove superiority to the older product—just functional equivalence. If a company wants to tout a new device as a breakthrough, why would it claim substantial equivalence to something 25 years old?

The reason is that the 510(k) process is easier and cheaper than seeking a premarket approval. The 510(k) process usually does not require clinical research. In the mid-1990s, a 510(k) application on average required 3 months for approval, and about $13 million. A premarket approval required, on average, about a year and $36 million. Both are modest compared with new drug approvals. The process by which the agency decides if something is “equivalent enough” to be approved by the 501(k) mechanism is subjective.

Because pre-1976 devices were not subject to any rigorous tests of clinical effectiveness, a newly approved device may be equivalent to something that has little or no therapeutic value. Doctors, patients, and payers therefore often have little ability to judge the value of new devices. As an example, the FDA still receives 510(k) applications for intermittent positive pressure breathing machines.[12] Yet a thorough review by the federal Agency for Health Care Policy and Research found that these devices offer no important benefits.[16]

How much do manufacturers take advantage of the easier 510(k) approach? Since 1976, nearly 98% of new devices entering the market in class II or III have been approved through the 510(k) process.[13] In 2002, the FDA reported 41 premarket approvals and 3708 approvals through the 510(k) process.[17]

“It is a good thing to learn caution from the misfortunes of others.”

“If you wish to succeed in life, make perseverance your bosom friend, experience your wise counselor, caution your elder brother, and hope your guardian genius.”

Dr. Richard A. Deyo, has published an article on this topic in 2004. His observations and references are most valuable for our Blog.

For fulll article go to:

JABFP March–April 2004 Vol.17 No.2 http://www.science.smith.edu/departments/Biochem/Chm_357/Articles/Drug%20Approval.pdf

HEALTH CARE POLICY

Author: Richard A. Deyo, MD, MPH

Despite many successes, drug approval at the Food and Drug Administration (FDA) is subject to gaps, internal tensions, and conflicts of interest. Recalls of drugs and devices and studies demonstrating advantages of older drugs over newer ones highlight the importance of these limitations. The FDA does not compare competing drugs and rarely requires tests of clinical efficacy for new devices. It does not review advertisements before use, assess cost-effectiveness, or regulate surgery (except for devices). Many believe postmarketing surveillance of drugs and devices is inadequate. A source of tension within the agency is pressure for speedy approvals. This may have resulted in “burn-out” among medical officers and has prompted criticism that safety is ignored. Others argue, however, that the agency is unnecessarily slow and bureaucratic. Recent reports identify conflicts of interest (stock ownership, consulting fees, research grants) among some members of the FDA’s advisory committees. FDA review serves a critical function, but physicians should be aware that new drugs may not be as effective as old ones; that new drugs are likely to have undiscovered side effects at the time of marketing; that direct-to-consumer ads are sometimes misleading; that new devices generally have less rigorous evidence of efficacy than new drugs; and that value for money is not considered in approval. J Am Board Fam Pract 2004;17: 142–9.

The process of drug development and approval by the United States Food and Drug Administration (FDA) was recently reviewed by Lipsky and Sharp.1 Using clinical literature and web sites addressing FDA procedures, that review concisely described the FDA’s history, the official approval process, and recent developments in drug approval. However, it did not delve into common misconceptions about the FDA, tensions within the agency, or conflicts of interest in the drug approval process. The rapidly growing business of medical device development, distinct from the drug approval process, also was not addressed. Although most aspects of the FDA review process are highly successful, its limitations deserve careful consideration, because they may have important implications for choosing treatments in practice.

Recent recalls of drugs and devices call attention to limitations of the approval process.2–4 Recent news about complications of hormone replacement therapy5,6 and new data supporting the superiority of diuretic therapy over newer, more expensive alternatives for hypertension7 emphasize gaps in the process. Clinicians should be aware of regulatory limitations as they prescribe treatments and counsel patients, so they have realistic ideas about what FDA approval does and does not mean.

Because controversies relating to internal conflicts or political issues are infrequently reported in scientific journals, this discussion draws not only on scientific articles, but also internet resources, news accounts, and interviews.The goal was not to be exhaustive, but to provide examples of tensions, conflicts, and gaps in the FDA process. As Lipsky and Sharp noted, the FDA approves new drugs and devices (as well as assuring that foods and cosmetics are safe).It monitors over $1 trillion worth of products, which represents nearly a fourth of consumer spending.1 In the medical arena, the basic goal of the FDA is to prevent the marketing of treatments that are ineffective or harmful.

However, the agency faces limitations that result from many factors, including the agency’s legal mandate, pressures from industry, pressures from advocacy groups, funding constraints, and varied political pressures.

Pressures for Approval

Perhaps the biggest challenge and source of friction for the FDA is the speed of approvals for drugs and devices. Protecting the public from ineffective or harmful products would dictate a deliberate, cautious, thorough process. On the other hand, getting valuable new technology to the public—to save lives or improve quality of life—would argue for a speedy process. Some consumer protection groups claim the agency is far too hasty and lenient, bending to drug and device company pressure. On the other hand, manufacturers argue that the agency drags its feet and kills people waiting for new cures. Says Kessler: “That’s been the biggest fight between the industry, the Congress, and the FDA over the past decade: getting products out fast” (L. Kessler, personal communication).

To speed up the review process, Congress passed a law in 1992 that allowed the FDA to collect “user fees” from drug companies. This was in part a response to AIDS advocates, who demanded quick approval of experimental drugs that might offer even a ray of hope.These fees, over $300,000 for each new drug application, now account for about half the FDA’s budget for drug evaluation, and 12% of the agency’s overall $1.3 billion budget.18 The extra funds have indeed accelerated the approval process.By 1999, average approval time had dropped by about 20 months, to an average of a year.In 1988, only 4% of new drugs introduced worldwide were approved first by the FDA.By 1998, FDA was first in approving two thirds of new drugs introduced worldwide.The percentage of applications ultimately approved had also increased substantially.18 Nonetheless, industry complained that approval times slipped to about 14 months in 2001.19

In 2002, device makers announced an agreement with the FDA for similar user fees to expedite approval of new devices, and Congressional approval followed with the Medical Device User Fee and Modernization Act.20 Critics, such as 2 former editors of the New England Journal of Medicine, argue that the user fees create an obvious conflict of interest. So much of the FDA budget now comes from the industry it regulates that the agency must be careful not to alienate its corporate “sponsors.”21

FDA officials believe they remain careful but concede that user fees have imposed pressures that make review more difficult, according to The Wall Street Journal .22 An internal FDA report in 2002 indicated that a third of FDA employees felt uncomfortable expressing “contrary scientific opinions” to the conclusions reached in drug trials.Another third felt that negative actions against applications were “stigmatized.”

The report also said some drug reviewers stated “that decisions should be based more on science and less on corporate wishes.”22 The Los Angeles Times reported that agency drug reviewers felt if drugs were not approved, drug companies would complain to Congress, which might retaliate by failing to renew the users’ fees 18 (although they were just re-approved in summer, 2002).This in turn would hamstring FDA operations and probably cost jobs.

Another criticism is that the approval process has allowed many dangerous drugs to reach the market. A recent analysis showed that of all new drugs approved from 1975 to 1999, almost 3% were subsequently withdrawn for safety reasons, and 8% acquired “black box warnings” of potentially serious side effects. Projections based on the pace of these events suggested that 1 in 5 approved drugs would eventually receive a black box warning or be withdrawn. The authors of the analysis, from Harvard Medical School and Public Citizen Health Research Group, suggested that the FDA should raise the bar for new drug approval when safe and effective treatments are already available or when the drug is for a non–life-threatening condition.2

According to The Los Angeles Times, 7 drugs withdrawn between 1993 and 2000 had been approved while the FDA disregarded “danger signs or blunt warnings from its own specialists. Then, after receiving reports of significant harm to patients, the agency was slow to seek withdrawals.” These drugs were suspected in 1002 deaths reported to FDA. None were life-saving drugs.They included, for example, one for heartburn (cisapride), a diet pill (dexfenfluramine), and a painkiller (bromfenac). The Times reported that the 7 drugs had US sales of $5 billion before they were recalled.18

After analysis, FDA officials concluded that the accelerated drug approval process is unrelated to the drug withdrawals. They pointed out that the number of drugs on the market has risen dramatically, the number of applications has increased, and the population is using more medications.3 More withdrawals are not surprising, in their view. Dr. Janet Woodcock, director of the FDA’s drug review center and one of the analysts, argued that “All drugs have risks; most of them have serious risks.”

She believes the withdrawn drugs were valuable and that their removal from the market was a loss, even if the removal was necessary, according to The Los Angeles Times.18 Nonetheless, many believe the pressures for approval are so strong that they contribute to employee burnout at FDA.In August 2002, The Wall Street Journal reported that 15% of the agency’s medical officer jobs were unfilled.22 Their attrition rate is higher than for medical officers at the National Institutes of Health or the Centers for Disease Control and Prevention. The Journal reported that the reasons, among others, included pressure to increase the pace of drug approvals and an atmosphere that discourages negative actions on drug applications.

Attrition caused by employee “burnout” is now judged to threaten the speed of the approval process. In 2000, even Dr. Woodcock acknowledged a “sweatshop environment that’s causing high staffing turnover.”18 FDA medical and statistical staff have echoed the need for speed and described insufficient time to master details.18,19 An opposing view of FDA function is articulated in an editorial from The Wall Street Journal, by Robert Goldberg of the Manhattan Institute. He wrote that the agency “protects people from the drugs that can save their lives” and needs to shift its role to “speedily put into the market place… new miracle drugs and technologies…. ” He argues that increasing approval times for new treatments are a result of “careless scientific reasoning” and “bureaucratic incompetence,” and that the FDA should monitor the impact of new treatments after marketing rather than wait for “needless clinical trials” that delay approvals.23

Thus, the FDA faces a constant “damned if it does, damned if it doesn’t” environment. No one has undertaken a comprehensive study of the speed of drug or device approval to determine the appropriate metrics for this process, much less the optimal speed. It remains unclear how best to balance the benefits of making new products rapidly available with the risks of unanticipated complications and recalls.

Postmarketing Surveillance of New Products

Although user fees have facilitated pre-approval evaluation of new drugs, the money cannot be used to evaluate the safety of drugs after they are marketed. Experts point out that approximately half of approved drugs have serious side effects not known before approval, and only post-marketing surveillance can detect them. But in the opinion of some, FDA lacks the mandate, the money, and the staff to provide effective and efficient surveillance of over 5000 drugs already in the marketplace. 24 Although reporting of adverse effects by manufacturers is mandatory, late or non reporting of cases by drug companies are major problems. Some companies have been prosecuted for failure to report, and the

FDA has issued several warning letters as a result of late reporting. Spontaneous reporting by practitioners is estimated to capture only 1% to 13% of serious adverse events. 25 Widespread promotion of new drugs—before some of the serious effects are known—increases exposure of patients to the unknown risks. It is estimated that nearly 20 million patients (almost 10% of the US population) were exposed to the 5 drugs that were recalled in 1997 and 1998 alone.26 The new law allowing user fees for device manufacturers does not have the same restriction on post-marketing surveillance that has hampered drug surveillance.

Conflicts of Interest in the Approval Process

Another problem that has recently come to light in the FDA approval process is conflict of interest on the part of some members of the agency’s 18 drug advisory committees. These committees include about 300 members, and are influential in recommending whether drugs should be approved, whether they should remain on the market, how drug studies should be designed, and what warning labels should say. The decisions of these committees have enormous financial implications for drug makers.

A report by USA Today indicated that roughly half the experts on these panels had a direct financial interest in the drug or topic they were asked to evaluate. The conflicts of interest included stock ownership, consulting fees, and research grants from the companies whose products they were evaluating. In some cases, committee members had helped to develop the drugs they were evaluating. Although federal law tries to restrict the use of experts with conflicts of interest, USA Today reported that FDA had waived the rule more than 800 times between 1998 and 2000.

FDA does not reveal the magnitude of any financial interest or the drug companies involved.27 Nonetheless, USA Today reported that in considering 159 Advisory Committee meetings from 1998 through the first half of 2000, at least one member had a financial conflict of interest 92% of the time. Half or more of the members had conflicts at more than half the meetings. At 102 meetings that dealt specifically with drug approval, 33% of committee members had conflicts.27 The Los Angeles Times reported that such conflicts were present at committee reviews of some recently withdrawn drugs.18

The FDA official responsible for waiving the conflict-of-interest rules pointed out that the same experts who consult with industry are often the best for consulting with the FDA, because of their knowledge of certain drugs and diseases. But according to a summary of the USA Today survey reported in the electronic American Health Line, “even consumer and patient representatives on the committees often receive drug company money.”28 In 2001, Congressional staff from the House Government Reform Committee began examining the FDA advisory committees, to determine whether conflicts of interest were affecting the approval process.29

Conclusion

Despite derogatory comments from some politicians and some in the industries it regulates, the FDA does a credible job of trying to protect the public and to quickly review new drugs and devices. However, pressures for speed, conflicts of interest in decision-making, constrained legislative mandates, inadequate budgets, and often limited surveillance after products enter the market mean that scientific considerations are only part of the regulatory equation. These limitations can lead to misleading advertising of new drugs; promotion of less effective over more effective treatments; delays in identifying treatment risks; and perhaps unnecessary exposure of patients to treatments whose risks outweigh their benefits.

Regulatory approval provides many critical functions. However, it does not in itself help clinicians to identify the best treatment strategies. Physicians should be aware that new drugs may not be as effective as old ones; that new drugs are likely to have undiscovered side effects at the time they are marketed; that direct-to-consumer ads are sometimes misleading; that new devices generally have less rigorous evidence of efficacy than new drugs; and that value for money is not considered in the approval process. If clinicians are to practice evidence-based and cost-effective medicine, they must use additional skills and resources to evaluate new treatments. Depending exclusively on the regulatory process may lead to suboptimal care.

REFERENCES

1.Lipsky MS, Sharp LK. From idea to market: the drug approval process.J Am Board Fam Pract 2001; 14:362–7.

2.Lasser KE, Allen PD, Woolhandler SJ, Himmelstein DU, Wolfe SM, Bor DH.Timing of new black box warnings and withdrawals for prescription medications. JAMA 2002;287:2215–20.

3.Friedman MA, Woodcock J, Lumpkin MM, Shuren JE, Hass AE, Thompson LJ.The safety of newly approved medicines: do recent market removals mean there is a problem? JAMA 1999;281:1728 –34.

4.Maisel WH, Sweeney MO, Stevenson WG, Ellison KE, Epstein LM.Recalls and safety alerts involving pacemakers and implantable cardioverter-defibrillator devices. JAMA 2001;286:793–9.

5.Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321–33.

6.Grady D, Herrington D, Bittner V, et al. Cardiovascular disease outcomes during 68 years of hormone therapy: Heart and Estrogen/progestin Replacement Study Follow-up (HERS II). JAMA 2002;288:49–57.

7.ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial.Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288:2981–97.

8.Echt DS, Liebson PR, Mitchell LB, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo.The Cardiac Arrhythmia Suppression Trial. N Engl J Med 1991;324:781–8.

9.Moore TJ. Deadly medicine: why tens of thousands of heart patients died in America’s worst drug disaster. New York: Simon and Schuster; 1995.

10.Petersen M. Diuretics’ value drowned out by trumpeting of newer drugs. The New York Times 2002 Dec 18;Sect A:32.

11.Gorelick PB, Richardson D, Kelly M, et al. Aspirin and ticlopidine for prevention of recurrent stroke in black patients: a randomized trial. JAMA 2003;289: 2947–57.

12.Gahart MT, Duhamel LM, Dievler A, Price R. Examining the FDA’s oversight of direct-to-consumer advertising. Health Aff (Millwood) 2003 Suppl W3– 120–3.

13.Ramsey SD, Luce BR, Deyo R, Franklin G. The 148 JABFP March–April 2004 Vol.17 No.2 limited state of technology assessment for medical devices: facing the issues. Am J Manag Care 1998;4 Spec No:SP188–99.

14.Merrill RA. Modernizing the FDA: an incremental revolution. Health Aff (Millwood) 1999;18:96–111.

15.Milestones in US food and drug law history. United States Food and Drug Administration. http://www. fda.gov/opacom/backgrounders/miles.html, accessed 8/19/02.

16.Handelsman H. Intermittent positive pressure breathing (IPPB) therapy. Health Technol Assess Rep 1991;(1):1 9.

17.FDA Center for Devices and Radiological Health. Office of Device Evaluation annual report 2002. Available at: URL:http://www.fda.gov/cdrh/annual/ fy2002/ode/index.html.

18.Willman D. How a new policy led to seven deadly drugs. The Los Angeles Times 2000 Dec 20;Sect. A:1.

19.Adams C, Hensley S. Health and Technology: drug makers want FDA to move quicker. Wall Street Journal 2002 Jan 29; Sect.B:12.

20.Adams C. FDA may start assessing fees on makers of medical devices. The Wall Street Journal 2002 May 21;Sect.D:6.

21. Angell M, Relman AS.Prescription for profit. The Washington Post 2001 Jun 20; Sect.A:27.

22.Adams C. FDA searches for an elixir for agency’s attrition rate. The Wall Street Journal 2002 Aug 19;Sect.A:4.

23. Goldberg R.FDA needs a dose of reform.The Wall Street Journal 2002 Sep 30;Sect.A:16.Available at: URL: http://www.aei.brookings.org/policy/page. php?id113

24.Moore TJ, Psaty BM, Furberg CD. Time to act on drug safety. JAMA 1998;279:1571–3.

25.Ahmad SR. Adverse drug event monitoring at the Food and Drug Administration: your report can make a difference. J Gen Intern Med 2003;18:57–60.

26.Wood AJJ. The safety of new medicines: the importance of asking the right questions. JAMA 1999;281:

1753–54.

27. Cauchon D.FDA advisers tied to industry.USA Today 2000 Sep 25; Sect.A:1.

28.Cauchon, D. Number of drug experts available is limited. Many waivers granted for those who have conflicts of interest. USA Today 2000 Sep 25;Sect. A:10.

29.Gribbin A. House investigates panels involved with drug safety. Mismanagement claims spur action. The Washington Times 2001 Jun 18;Sect.A:1.

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Prostate Cancers Plunged After USPSTF Guidance, Will It Happen Again?

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, FDA Regulatory Affairs, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, tagged Archives of Internal Medicine, Prostate cancer, Prostate cancer screening, Prostate-specific antigen, PSA, StataCorp, United States Preventive Services Task Force on July 31, 2012| 5 Comments »

Prostate Cancers Plunged After USPSTF Guidance, Will It Happen Again?

Reporter: Aviva Lev-Ari, PhD, RN

Declines in Prostate Cancer Incidence After Changes in Screening Recommendations

David H. Howard, PhD

Arch Intern Med. 2012;():1-2. doi:10.1001/archinternmed.2012.2768

On August 5, 2008, the US Preventive Services Task Force (USPSTF) recommended against screening men 75 years or older for prostate cancer.¹For men younger than 75 years, the USPSTF maintained its previous recommendation: “ . . . the evidence is insufficient to recommend for or against routine screening for prostate cancer. . . ”²^(p915) (although this recommendation was changed to “do not screen” younger men in the 2011 guidelines). This study evaluates trends in prostate cancer incidence following the release of the 2008 USPSTF recommendation. If the revised recommendation led to a decline in prostate cancer screening rates, there should be a corresponding decline in the incidence of early-stage tumors among men 75 and older relative to trends in the incidence of late-stage tumors and early-stage tumors in younger men.

Methods

I measured trends in prostate cancer incidence rates by age group using the Surveillance, Epidemiology and End Results (SEER) 18 registry data, covering 28% of the US population. The SEER registries collect information on all newly diagnosed cancer cases in their respective catchment areas.

Prostate tumors were identified using International Classification of Diseases for Oncology version 3 code 619. I classified cases by stage at diagnosis using the derived American Joint Committee on Cancer summary stage variable: early (T1 or T2), late (T3 or T4), or unknown. I grouped patients into 3 age categories (30-64 years, 65-74 years, and 75 years and older). I calculated incidence rates per 100 000 persons, standardized within age categories by age (in 5-year age groups), race (white, black, American Indian, or other), and ethnicity (Hispanic or not Hispanic) to the 2009 population. I used an unpaired t test for proportions to assess the significance of differences in rates between years. The data were analyzed in Stata version 11 (StataCorp) statistical software.

Results

The data included 254 184 prostate cancer cases. There were 198 417 early-stage cases, 34 695 late-stage cases, and 21 072 cases of unknown stage. There were 109 053 cases (all stages) among men aged 30 to 64 years, 91 868 cases among men aged 65 to 74 years, and 53 263 cases among men 75 years and older.

The Figure displays the age and race/ethnicity-adjusted incidence rates of early-stage tumors among men aged 65 to 74 years (the upper line) and 75 years and older (the lower line). The trend lines generally mirror each other, but there is a sudden decrease in the incidence of early-stage tumors among men 75 and older after the release of the revised USPSTF recommendation.

Figure. Trends in the incidence of early-stage prostate tumors by age group. Rates are standardized by 5-year age groups and race/ethnicity to the 2009 population. Source: analysis of Surveillance, Epidemiology and End Results (SEER) 18 registry data. USPSTF indicates US Preventive Services Task Force.

View Large | Save Figure | Download Slide (.ppt)

Between 2007 and 2009, the adjusted incidence rate for early-stage tumors among men 75 years and older decreased from 443 to 330 per 100 000 (−25.4%; P < .001). The absolute number of cases declined from 8137 to 6162. The incidence of late-stage tumors decreased from 83 to 71 (−14.3%; P < .001), and the incidence of tumors with unknown stage decreased from 124 to 103 (−16.8%; P < .001). The incidence of early-stage tumors among men aged 65 to 74 years decreased from 697 to 591 (−15.2%; P < .001). The incidence of early-stage tumors among men aged 30 to 64 years decreased from 105 to 93 (−11%; P < .001). Incidence trends for all age and stage groups are given in the eTable.

July 25, 2012 — Nick Mulcahy reports in

http://www.medscape.com/viewarticle/768073?src=nldne

In the past, clinicians and the public have heeded the advice of the United States Preventative Services Task Force (USPSTF) about prostate cancer screening, suggests researchpublished online July 23 in the Archives of Internal Medicine.

After the group’s 2008 guidance, which recommended against screening men older than 75 years, the incidence of early-stage disease in older men plunged 25% in the United States.

“There was an immediate decline in the incidence of early-stage prostate cancer tumors among men 75 years and older after the USPSTF recommended against screening this group,” writes author David Howard, PhD, from the Department of Health Policy and Management at Emory University in Atlanta, Georgia.

The incidence of early-stage disease is an indicator of the amount of prostate-specific antigen (PSA) testing in a population, he explained.

Dr. Howard found that from 2007 to 2009, the adjusted incidence rate for early-stage tumors in men 75 years and older decreased from 443 to 330 per 100,000 (−25.4%; P < .001). The absolute number of cases declined from 8137 to 6162.

Dr. Howard used data from the Surveillance, Epidemiology, and End Results (SEER) 18 registry, which collects information on newly diagnosed cancer cases in catchment areas.

He challenges recent results that indicated that there was no change in PSA screening rates from 2005 to 2010 (JAMA. 2012;307:1692-1694). The data source for that study was the National Health Interview Surveys, in which American residents self-report health behaviors and diseases. “Self-reported PSA testing measures have poor sensitivity and specificity,” scolds Dr. Howard.

An immediate question arises from Dr. Howard’s analysis: Will it happen again because of the 2012 USPSTF recommendation against routine testing for all healthy men?

In an unrelated essay (J Clin Oncol. 2012;30:2581-2584), a group of experts assert that the answer is no.

The USPSTF’s “blanket rejection” of the PSA test is “unlikely to influence practice,” according to Sigrid Carlsson, MD, PhD, from the Memorial-Sloan Kettering Cancer Center in New York City and Göteborg University in Sweden, and colleagues. Dr. Carlsson and her fellow experts wrote an essay criticizing the new USPSTF guideline for a number of “very important errors,” as reported by Medscape Medical News.

“PSA testing is not likely to go away,” wrote Dr. Carlsson and coauthors.

Dr. Howard voiced similar thoughts in an email to Medscape Medical News.

“Physicians are probably more willing to discontinue screening older patients. There might be more resistance to discontinuing screening among younger, healthier men,” he said.

But Dr. Howard also said: “I think it will have an impact. There is growing publicity about the problem of ‘overdiagnosis’, which might make physicians and some patients more receptive to the USPSTF recommendation.”

The recently published PIVOT study might also contribute to the way the new guidance is received, noted Dr. Howard. This major randomized controlled trial found that prostatectomy did not improve survival significantly, compared with observation, in men with localized disease. “This research also casts doubt on the benefits of early detection, which may amplify the impact of the USPSTF recommendation,” said Dr. Howard about PIVOT.

Nonetheless, “many men will continue to receive regular PSA tests,” he added.

More Details

In addition to finding that the rate of early-stage prostate cancers dropped among older men after the 2008 recommendation, Dr. Howard found that other indicators of PSA testing also dropped.

The incidence of late-stage tumors decreased by 14.3% (P < .001), and the incidence of tumors of unknown stage decreased by 16.8% (P < .001). The incidence of early-stage tumors in men 65 to 74 years decreased by 15.2% (P < .001); in men 30 to 64 years, the incidence decreased by 11% (P < .001).

Overall, Dr. Howard found that 254,184 prostate cancer cases were newly diagnosed during the study period. There were 198,417 early-stage cases, 34,695 late-stage cases, and 21,072 cases of unknown stage. There were 109,053 cases (all stages) in men 30 to 64 years of age, 91,868 cases in men 65 to 74 years, and 53,263 cases in men 75 years and older.

As noted above, the incidence rate trends turned sharply downward in 2009, after the 2008 USPSTF report.

REFERENCES

METHODS | RESULTS | COMMENT | AUTHOR INFORMATION | REFERENCES

US Preventive Services Task Force. Screening for prostate cancer: US Preventive Services Task Force recommendation statement. Ann Intern Med. 2008;149(3):185-191

US Preventive Services Task Force. Screening for prostate cancer: recommendation and rationale. Ann Intern Med. 2002;137(11):915-916

Prasad SM, Drazer MW, Huo D, Hu JC, Eggener SE. 2008 US Preventive Services Task Force recommendations and prostate cancer screening rates. JAMA. 2012;307(16):1692-1694

Hall HI, Van Den Eeden SK, Tolsma DD, et al. Testing for prostate and colorectal cancer: comparison of self-report and medical record audit. Prev Med. 2004;39(1):27-35

Chan EC, Vernon SW, Ahn C, Greisinger A. Do men know that they have had a prostate-specific antigen test? accuracy of self-reports of testing at 2 sites. Am J Public Health. 2004;94(8):1336-1338

Guerra CE, Jacobs SE, Holmes JH, Shea JA. Are physicians discussing prostate cancer screening with their patients and why or why not? a pilot study. J Gen Intern Med. 2007;22(7):901-907

Linder SK, Hawley ST, Cooper CP, Scholl LE, Jibaja-Weiss M, Volk RJ. Primary care physicians’ reported use of pre-screening discussions for prostate cancer screening: a cross-sectional survey. BMC Fam Pract. 2009;1019

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Biosimilars: Intellectual Property Creation and Protection by Pioneer and by Biosimilar Manufacturers

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biomarkers & Medical Diagnostics, BioSimilars, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Computational Biology/Systems and Bioinformatics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, FDA Regulatory Affairs, Genome Biology, Health Economics and Outcomes Research, International Global Work in Pharmaceutical, Medical and Population Genetics, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Analytics, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Investment, Population Health Management, Genetics & Pharmaceutical, Proteomics, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, tagged Biologics Price Competition, Biosimilar, BPCIA, FDA, Food and Drug Administration, Innovation Act, Intellectual property, Public Health Service Act on July 30, 2012| 9 Comments »

Biosimilars: Intellectual Property Creation and Protection by Pioneer and by Biosimilar Manufacturers

Curator: Aviva Lev-Ari, PhD, RN

UPDATED on 5/19/2023

The state of biosimilars in 2023

by Davide Savenije, Editor-in-Chief at Industry Dive

Although the U.S biosimilars market has fallen short of expectations since its first product approval in 2015, more have poured onto the market after a slow start. Greater price competition could emerge as more biosimilars of each drug begin to launch.

INCLUDED IN THIS TRENDLINE

Big pharma’s looming threat: a patent cliff of ‘tectonic magnitude’

AbbVie weathers first months of biosimilar challenge to top-selling Humira

Acquired patents aid J&J defense of top-selling drug from biosimilar challenge

Our Trendlines go deep on the biggest trends. These special reports, produced by our team of award-winning journalists, help business leaders understand how their industries are changing.

SOURCE

https://www.biopharmadive.com/trendline/biosimilars/47/?utm_source=BP&utm_medium=Library&utm_campaign=ThermoFisher&utm_term=BioPharma%20Dive

For Financial Aspects of Biosimilars, go to:

Biosimilars: Financials 2012 vs. 2008

http://pharmaceuticalintelligence.com/2012/07/30/biosimilars-financials-2012-vs-2008/

For CMC and Regulatory Affairs of Biosimilars, go to:

Biosimilars: CMC Issues and Regulatory Requirements

http://pharmaceuticalintelligence.com/2012/07/29/biosimilars-cmc-issues-and-regulatory-requirements/

In this post we focus on the Legal Scene of Intellectual Property Creation & Protection by Pioneer & by Biosimilar Manufacturers.

The regulatory pathway for biosimilars has an impact on biopharma R&D, M&A and valuation of companies and products. Industry and investors were uncertain if biosimilar will be approved, the impact a new biosimilar will have on rate of return and sales of pioneer innovators which are big pharma with dedicated divisions to biosimilars as well as on new entrants as biosimilar manufacturers.

Biosimilars, aka biogeneric, biocomparable or follow-on biologic are different than traditional pharmaceuticals, aka small molecules produced by chemical reactions, subjected to generic competition. Biosimilars include proteins produced by genetically engineered organisms, have not been challenged by generic competion.The generic competition provisions of the Drug Price Competition and Patent Term Restoration Act of 1984 (Hatch-Waxman Act) apply to products approved under the Food, Drug, and Cosmetic Act, which include small molecule pharmaceuticals, but not to products approved under the Public Health Service Act, which include biologics.

It is estimated that, within a few years, biologics will be half of the biopharmaceutical market. As a result there have been mounting calls for a biosimilar pathway for companies obtaining Food and Drug Administration (FDA) approval of generic versions of existing biologics based upon lesser showings of safety and efficacy than is required for a pioneer biologic.

Like Hatch-Waxman Act for generic drugs, The Biologics Price Competition and Innovation Act (BPCIA) aka Biosimilar Act of 2009 (1) establishes standards for application and approval; (2) provides a term of data exclusivity; and (3) establishes a scheme for handling patent disputes. The similarities, however, end with these broad constructs, as the details involved with each are quite different.

Patent Disclosure Requirements

The Biosimilar Act imposes completely new disclosure requirements for patents that are demanding and time-sensitive, and it imposes these requirements on both pioneer and biosimilar manufacturers. These requirements will be required after submission of a biosimilar application and will demand sophisticated legal counseling and planning. These requirements are as follows:

• The biosimilar applicant must provide a copy of the application to the pioneer manufacturer (reference product sponsor) within 20 days of being notified that its application has been accepted by the FDA.

• The pioneer manufacturer must provide the applicant with a list of patents that it believes “could reasonably be asserted” with respect to the pioneer product within 60 days of receiving a copy of the application. The list must identify which patents the pioneer manufacturer would be prepared to license to the biosimilar applicant.

• The biosimilar applicant must provide the pioneer manufacturer with a detailed statement describing its opinion that any patent listed is invalid, unenforceable, or will not be infringed by the commercial marketing of the biosimilar, or a statement that it does not intend to begin commercial marketing of the biosimilar before the expiration of the listed patent(s), within 60 days of receiving the list of patents.

• The pioneer manufacturer must provide the biosimilar applicant with a detailed statement describing its opinion that its patent(s) will be infringed by the biosimilar, as well as a response concerning the validity and enforceability of its patent(s) within 60 days of receiving the biosimilar applicant’s detailed statement.

• The biosimilar applicant must notify the pioneer manufacturer 180 days before the first commercial marketing of the biosimilar. The pioneer manufacturer may then seek a preliminary injunction.

After these required exchanges, the act requires good faith negotiations by the parties to agree on which patents will be the subject of any infringement action. Within 30 days of either agreeing on this list of patents, or exchanging each party’s final list of patents, the pioneer manufacturer must bring an infringement action. The pioneer manufacturer also has 30 days to amend this list after the issuance, or exclusive licensing, of a new patent that it believes is infringed by the biosimilar. If the pioneer manufacturer prevails in this action before approval of the biosimilar, the court must enter a permanent injunction prohibiting further infringement.

Failure to bring an infringement action within the 30-day mandate (or bringing an infringement action that was dismissed without prejudice or was not prosecuted to judgment in good faith) will result in the available remedy being limited to a reasonable royalty only. Finally, failure by the pioneer manufacturer to timely include a relevant patent in the exchanged list will preclude the pioneer manufacturer from later bringing an infringement action against the biosimilar applicant with respect to that undisclosed patent.

Intellectual Property Considerations

As a result, it is feasible that a biosimilar may be similar enough to qualify as a biosimilar under the Biosimilar Act but not similar enough to be covered by a patent claim. Accordingly, pioneer manufacturers should take care in obtaining valid claims that afford broad patent protection of their biologics. To do so, pioneer manufacturers should consider, for example, protecting not only the biologic itself but also, if possible, the target molecule(s) of the biologic, methods of use and methods of production. In addition, pioneer manufacturers should also contemplate how their biologics may be modified and consider obtaining patent protection for those modifications. While this is generally a common practice in patent law, it has been less important in pharamceuticals, where the focus has been on the patents that protect the drug itself rather than methods of its manufacture, and on obtaining protection from a generic (a bioequivalent drug, rather than a less equivalent drug that could treat the same condition).

Biosimilar manufacturers, on the other hand, should analyse how the pioneer’s biologic is protected by one or more patents and consider how they may be able to escape patent protection. Biosimilar manufacturers should also be careful of what admissions they make in regard to what is and is not equivalent in an application under the Biosimilar Act. Such admissions may be considered by manufacturers of the pioneer biologic for possible infringement positions. Under the Biosimilar Act, there is a certain amount of protection afforded through data exclusivity for a pioneer biologic. Pioneer biologic manufacturers, however, should not solely rely on this period of exclusivity for protection. Not only may patent protection go beyond the protection afforded by the data exclusivity period for a pioneer biologic, but an additional data exclusivity period may not be available under the Biosimilar Act. As a result, it is important for pioneer manufacturers to consider obtaining patent protection for improvements to their pioneer biologic.

Likewise, biosimilar manufacturers should also seek patent protection for their biosimilars and improvements to them, and consider the pioneer biologic and associated patents in doing so. Patent protection may be available for biosimilar biologics even when data exclusivity under the new act is not. In regard to the patent disclosure requirements, the scheme of the new act appears to avoid many of the problems that have arisen under the Hatch-Waxman Act for generic pharmaceuticals, such as the numerous issues regarding the requirement to list relevant patents in the Orange Book.

However, the completely new patent disclosure scheme for biosimilars will take years for the FDA and the courts to sort out. In the end, it may very well be more burdensome on the parties than the Hatch-Waxman Act, which has spawned a tremendous amount of litigation. At the very least, the patent provisions of the Biosimilar Act establish demanding and time-sensitive disclosure requirements for both the pioneer and biosimilar applicant. Given the detail required and the complexity of the issues, both parties should conduct the necessary investigation and analysis well before a biosimilar application could be filed. Some steps that may be taken include: identifying all relevant patents, determining expiration dates and potential patent term extensions, and identifying patent owners and licenses. Based on the investigation and analysis, both parties should develop detailed infringement, validity, and enforceability positions before receiving the other party’s patent list or positions. Failing to take early action will likely result in a party rushing to prepare the very detailed statements required by the law for both parties, running the serious risk of making a potentially determinative mistake. Both parties also face penalties for failing to comply with the disclosure requirements.

In all, it will be important for pioneer and biosimilar manufacturers to fully understand their patent portfolios as well as those of their competitors and to review these portfolios regularly. The requirements of the Biosimilar Act will necessitate sophisticated and extensive legal counseling, active portfolio diligence, and time-sensitivity

http://www.wolfgreenfield.com/files/2426_biosimilars_2_final_pdf.pdf

http://www.managingip.com/Article/3047226/Search/An-overview-and-update-on-biosimilars.html?Home=true&Keywords=Biosimilars&Brand=Site&tabSelected=True

Greater clarity in the biopharma and pharma market place was achieved on June 28, 2012 when the US Supreme Court has upheld ObamaCare, ensuing that the pathway for biosimilars included with the law will remain intact.

The US paved the way for biosimilar approval in 2012 as part of the Patient Protection and Affordable Care Act (PPACA). A major element of the healthcare reform law is The Biologics Price Competition and Innovation Act (BPCIA) aka Biosimilar Act of 2009 provision of that bill said that biological products that are demonstrated to be highly similar (biosimilar) to or interchangeable with an FDA-licensed biological product may be approved under an abbreviated pathway similar to the process for small molecule generics.

With the upheld ObamaCare, critical parts of the PPACA constitutional, and with it the BPCIA giving the FDA authority to approve biosimilars.

Had the PPACA been stricken in part or in its entirety, it would have presented obstacles to the BPCIA surviving in its present form. The US government has been critical of the 12-year data exclusivity period for Pioneer Innovators, calling for it to be shortened to 7 years (12 years is favorable to Pioneer Innovators and less favorable for Biosimilar manufacturers). The upheld ObamaCare, PPACA and BPCIA, constitutional, has prevented a multiyear delay in biosimilar approval. Thus, it was the best scenario for the biologics industry.

BPCIA provides the approval of biological products as biosimilar or interchangeable (BPCIA 351(k)). As part of the FDA’s approval process, biosimilar products would need to produce the same clinical effect and if a multi-dose product, not present any greater safety or efficacy risk to patients in switching from the reference product. There would have to be “clinically meaningful differences” between the pioneer biologic reference product and the biosimilar product in order to gain FDA approval.

Congress granted the FDA flexibility for approval standards for biosimilars, i.e., what type of clinical studies required, what differences in approval process from biologics license applications (BLA) are appropriate.

1. Pioneer inventors are granted 12 years of data exclusivity, barring FDA approval of a 351 (k) application from “the date on which the reference product was first licensed”

2. An application can’t be submitted to the FDA until 4 years after the date on which the BLA for the reference product was first granted.

3. FDA sets approval requirements unless FDA waives them: analytical studies demonstrating the biosimilar is highly similar to the reference product, animal studies, a clinical study sufficient to demonstrate safety, purity, potency, same mechanism of action, route of administration, dosage form and strength.

Hatch-Waxman Act for generic drugs patent challenge provisions are different from BPCIA‘s patent challenge provisions.

BPCIA require “negotiation” of patent disputes and exchanges of patent information between parties prior to instituting patent litigation.
BPCIA mandates risk evaluation and mitigation strategy (“REMS”) requirements, shall apply to biosimilars as they do to reference pioneer biologic.
Reimbursemwnt for biosimilars is set at Average Sales Price (ASP) plus 6% of the amount determined for the amount determined for the reference pioneer biologic.
BPCIA allows for imposition of user fees to review biosimilars
Naming biosimilars: generic vs. proprietary naming requirements for drug safety and/or recalls, tracking adverse events, as well as reimbursement
Unanswered, if a biosimilar applicant needs to provide data on al approved indications of the reference product, and can a biosimilar be better than a reference product (i.e., “biobetters”), if so in what way (e.g., safety or efficacy).

On 2/9/2012 – FDA issued 3 draft guidance documents intended to facilitate the submission of marketing applications for biosimilars

1. Biosimilars Q&A: provide guidance on the content of 351(k) applications. Recommendations that sponsors meet early with FDA to discuss plans. Guidance sets out the FDA’s current view that comparative animal or clinical data developed using non-US-licensed product can provide evidence that proposed product is biosimilar to a US-licensed reference product.

2. Biosimilars Scientific Guidance – three approaches to establish demonstrated biosimilarity.

a. “stepwise” approach comparison of proposed product with reference product with respect to structure, function, animal toxicity, human pharmacokinetics (PK) and pharmacodynamics (PD), cinical immunogenicity, and clinical safety and effectiveness.

b. “totality-of-the-evidence” approach

c. “general scientific principles” in conducting comparative structural and functional analysis, animal testing, human PK and PD studies, clinical immunogenicity assessment and clinicall safety and effectiveness studies (study design issues)

3. Biosimilar Quality Guidance provides directions on analytical studies assessing if the proposed biosimilar protein product and the reference product are “highly similar” Guidance suggests that there may be an opportunity for pioneer innovators to argue that current technology does not permit for demonstration of “biosimilarity” of a potentially competitive product in a manner adequate to gain approval under 351(k), thus necessitating the filing of full BLA.

Outstanding issues under BPCIA’s provisions related to marketing and development could affect biopharma investment:

1. effects on coverage and reimbursement of the pioneer biologic based on approval of a biosimilar, reimbursement of biosimilars themselves

2. biosimilars and not expressly treated in the new act under Medicare Part B, Medicare Drug Pricing Program, Medicaid, 340B program.

3. non clear is biosimilars will constitute “multi-source drugs.”

Unlike the generic drugs market, the biosimilars market is likely to have a smaller number of entrants, greater costs of applications and testing, less reduction in price from that of a pioneer biologic and necessity of marketing staff.

It is unclear when the cost of the drug will become a switching factor in purchasing a biosimilar. purchaser resistance note withstanding price advantage did occur in the past. There eexist potential purchaser/payor concerns regarding interchangeability, safety, efficacy (i.e., potency). There is concern over evergreening strategy by pioneer inventors to use drug modifications to extend the exclusivity period thus, deterring the entrance of biosimilars.

In June 2011, the European Medicines Agency (EMA) and FDA issued a joint report noting the interactions between the two agencies, when a biosimilar version of a mococlonal antibody, Remicade was filed in the EU.

Defining Protein Therapeutics

FDA promises a risk-based “totality-of-the-evidence” approach to reviewing biosimilars. Novo Nordisk and Pfizer urged FDA to rethink its definition of proteins as excluding alpha amino acid polymers with fewer than 41 amino acids. Jim Shehan, Novo Nordisk’s corporate vp, legal, government, and quality affairs, noted that the definition clashed with statutes defining biological products as including any polypeptide except for those that are chemically synthesized.

“We believe they have selected an arbitrary cutoff,” Shehan told GEN. “It can conflict with the statutory language and it really isn’t grounded in science either,” an exception, he said, to the guidance’s overall focus on respect for science and patient safety. “In broad strokes, they met the mark in seeming to have a healthy respect for the need to have data in order for biosimilars to come to market.”

F. Owen Fields, Ph.D., Pfizer vp, worldwide regulatory strategy, worldwide R&D, suggested a case-by-case review of proteins with 40 or fewer amino acids. He cited Nisin, a 37-amino-acid polypeptide derivative approved by FDA as a food preservative, as an example among natural peptides best treated as proteins because of their potential for use as substrates for new drug development. “There are structures less than 41 amino acids that present regulatory science issues that are more similar to biologically synthesized proteins than to chemically synthesized peptides,” Dr. Fields pointed out at the hearing.

Keeping Trade Secrets Secret

Abbott called for additional FDA efforts to protect trade secrets of reference drugs during agency review of biosimilar applications. “Safeguards are needed to ensure that the agency doesn’t unintentionally, inadvertently, but nevertheless impermissibly use or disclose to a biosimilar applicant an innovator’s trade secrets,” Neal Parker, an Abbott attorney, said at the hearing.

Among safeguards suggested by Parker were FDA developing IT systems tracking employee involvement with BLAs and biosimilar applications, creating policies and procedures and training employees in them, and preventing FDA reviewers “significantly” involved in reviewing specific U.S.-licensed innovator BLA products from any biosimilar application review activities or any communications with biosimilar applicants seeking to rely on those same reference products.

Abbott recently submitted a citizen’s petition requesting that the agency not consider any applications for biosimilars based on biologic reference products for which a BLA was submitted before March 23, 2010, the date that President Barack Obama signed the Biologics Price Competition and Innovation Act. The request would effectively shield Abbott’s mAb therapeutic and biggest-selling treatment Humira from biosimilar competition. The company is about to spin off its brand-name drug development operations, remaining as a maker of medical equipment and generic drugs.

Fine-Tuning Data Requirements

Kalyan R. Anumala, Ph.D., senior director of Therapeutic Proteins, suggests that the agency should only require Phase II and III trials where it establishes a need after reviewing a submission. He also said the agency should encourage new characterization methods rather than clinical trials.

Also calling for additional characterization methods is the only U.S. company marketing biosimilar drugs, Hospira. Its products include anemia treatment Retacrit in the EU and biosimilar filgrastim product Nivestim, sold in the EU and Australia for stimulating production of white blood cells in patients receiving cytotoxic chemotherapy.

Samant Ramachandra, M.D., Ph.D., Hospira’s senior vp, R&D and regulatory and medical affairs and CSO, also urged FDA to account for reference product variability and clarify the required approach to show clinical immunogenicity assessment.

Dr. Ramachandra and James M. Roach, M.D., svp and CMO of Momenta Pharmaceuticals, urged FDA to permit the use of bridging data in return for allowing non-U.S. reference products. “This is critical if the goal is to implement a global development program that is feasible to conduct,” Dr. Roach added. Eli Lilly’s Gregory C. Davis, Ph.D., pressed FDA for more guidance on the type and extent of bridging data that would be permissible.

Abbott, by contrast, said data from studies involving a foreign comparator product cannot be considered pivotal if the foreign comparator is different from the U.S. reference product. FDA has stated that clinical comparisons with a non-U.S. licensed product do not provide an adequate basis to support interchangeability.

Jay P. Siegel, M.D., chief biotechnology officer and head of global regulatory affairs for Janssen Pharmaceutical, echoed many brand-name drug developers by urging FDA to maintain the draft guidance’s standard for interchangeability. Applicants would have to demonstrate biosimilarity and the ability of the biological product to produce the same clinical result as the reference product in any given patient.

If biosimilarity is established, it should also be extrapolated to pediatric populations, said Karl Heinz Emmert, Ph.D., managing director for Merckle Biotec, a Teva Group member. Dr. Emmert contended that FDA need not require clinical studies of pediatric populations with a biosimilar product. That differs from the thinking of Pfizer, which while supportive of extrapolations between populations within an indication, suggested an exception: diseases where pediatric pathophysiology differs from that of adults.

With regard to manufacturing concerns, Paul Eisenberg, an Amgen svp, argued in part: “Requiring the maintenance of biosimilarity over time would inhibit manufacturing and quality improvements and unduly burden industry without benefiting patients.” Mark McCamish, M.D., Ph.D., head of global biopharmaceutical development for Sandoz Biopharmaceuticals, disagreed.

Determining Label Details

Amgen did not address manufacturing issues in testimony but focused instead, along with several other companies, on how biosimilars should be identified and labeled to ensure accurate tracking and tracing. Suggestions included biosimilar names sharing a common root but having a unique suffix and/or prefix to denote biosimilarity and interchangeability.

“Having unique names will avoid unintended substitution, minimize risk of medication errors, allow for essential elements of pharmacovigilance such as traceability and follow-up of adverse drug reactions, as well as facilitate prescriber-patient decision making,” commented Michelle Rohrer, Ph.D., vp, U.S. regulatory affairs at Genentech.

Teva’s Dr. Emmert and Ahaviah Diane Glaser, vp for policy and strategic alliances with the Generic Pharmaceutical Association (GPhA), noted, however, that while all biologics should be uniquely tracked, biosimilars should not require unique International Nonproprietary Names (INNs) from their reference products. Glaser said different INNs would impede market competition because it would likely require a different marketing campaign, thus raising costs, and would also complicate collection of global safety data and could increase medical errors.

Embracing Biosimilars

Further guidance on naming biosimilars and interchangeables was one point agreed upon by industry and patient groups, so it’s likely FDA will oblige. That’s the easy issue for the agency. Tougher will be how to balance shepherding biosimilars and interchangeable products to market without sacrificing patient safety.

“If FDA issues product-specific guidances with very clear mandates that to get a biosimilar approved, you need to run a Phase III-like trial of X size, evaluating X, Y, and Z, it takes away from the incentive to put that much more time and scientific thought into proving from a structural and functional basis that you have the same compound,” Dr. Roach of Momenta told GEN.

Years ago EMA developed solid scientific guidelines, then product-specific rules that succeeded in bringing biosimilars to Europe. Sandoz’ Dr. McCamish credited EMA’s consistent standards with health authorities embracing biosimilars. It’s a lesson the U.S. will have to learn as FDA builds the pathway for biosimilars to finally reach the American market.

http://www.genengnews.com/insight-and-intelligenceand153/fda-s-hearing-for-biosimilars-showcased-issues-ranging-from-definitions-to-study-requirements-to/77899607/

On February 9, FDA issued long-awaited guidelines designed, according to FDA drug division director Janet Woodcock, M.D., “to help industry develop biosimilar versions of currently approved biological products.” Paul Calvo, Ph.D., a director at Sterne, Kessler, Goldstein & Fox, told GEN, “There were no major surprises” in the guidelines.

“It is clear that FDA wants to move forward with biosimilar approvals and they will be looking to a totality of the evidence as the standard for a determination of biosimilarity.” He also commented that FDA wants a constant dialog with biosimilar sponsors and all the structural and functional data up front. “Their goal for the up-front data is to be involved in design of the clinical trials in order to maximize the data provided.”

FDA’s new documents describe a step-wise approval pathway, starting with extensive analytical, physico-chemical, and biological characterization data that will have to demonstrate a high degree of similarity to the reference product. FDA will evaluate that data and then provide advice to the sponsor on the extent and scope of animal and human testing needed to show biosimilarity. The agency will consider multiple factors in making study determinations, including product complexity, formulation, stability, structure-function relationships, manufacturing process, and clinical experience with the reference product.

While the pathway to the agency’s decision making will be abbreviated, “it will depend on existing data,” Rachel Sherman, M.D., director of the Office of Medical Policy in FDA’s Center for Drug Evaluation and Research, said during a conference call. “We do not want companies repeating studies that do not need to be done.” As to whether most biosimilar applicants will be expected to carry out clinical trials, decisions will be made on a product by product basis.

Another topic of note is that the FDA has said that there could be extrapolation of clinical data to other diseases to give companies developing biosimilars approval for use in multiple indications for a given product. “But for therapeutics like Rituxan with two disparate indications, one for lymphoma and another for rheumatoid arthiritis, two sets of clinical trials will likely be required,” Dr. Calvo explained.

Interchangeability and Exclusivity

Importantly for the industry, the guidance documents indicate that the agency hasn’t settled some important biosimilars policy questions, including requirements for demonstrating interchangeability of a biosimilar with a reference product and terms for establishing the exclusivity period for pioneer biologics.

The Patient Protection and Affordable Care Act, signed into law by President Barack Obama on March 23, 2010, mandated the creation of an abbreviated approval pathway for biosimilars and proposed a 12-year data exclusivity period. The president’s budget proposal for fiscal 2013 released February 13, however, suggests that exclusivity should be lowered to seven years.

With regard to interchangeability, FDA states that it “is continuing to consider the type of information sufficient to enable FDA to determine that a biological product is interchangeable with the reference product.” Dr. Calvo explained that “interchangeability is important because it provides for a period of market exclusivity as well for automatic substitution of the interchangeable for the approved biologic without intervention from the prescribing physician.”

“However,” Dr. Calvo added, “given how new the whole process for biosimilar approval is, it would have been surprising if the FDA would have said there would not be any issues in determining interchangeability.” But, he noted, the agency has said that right now it doesn’t have the scientific ability to approve biosimilars as interchangeable.

An Amgen spokesperson commented that “FDA’s acknowledgement that determining interchangeability is scientifically difficult at this time is important. Patient safety does not stop at approval, and Amgen believes that post-approval activities including ongoing monitoring are essential to patient safety.”

Dr. Sherman believes that the hurdles for interchangeability would be high. Biologic drugs carry the added risk of prompting an immune response, she noted, and the FDA would “almost certainly” require clinical trials in which a patient is switched from the branded drug to the biosimilar and back to rule out the risk of triggering the immune system.

Potential Cost Savings

Dr. Calvo pointed out that “the ability to have a high level of FDA input will likely increase the chance that biosimilars will soon enter the U.S. market.” However, he added, the price erosion that occurs with small molecules “will not happen for biosimilars to even close to the extent that it occurs with small molecules, mainly because there will not be a mechanism for automatic substitution and because clinical studies will be required at least to some degree.”

For more complex products such as antibody conjugates or highly purified protein mixtures, “it is highly likely that more sophisticated manufacturing and analytical methods and possibly clinical trials will be required, therefore increasing costs for biosimilar entrants,” Jefferies analyst Biren Amin said in a note to clients. “This could apply to products like Seattle Genetics’ Adcetris or ImmunoGen and Roche’s T-DM1.”

The Congressional Budget Office still estimates that biosimilars would save the government $25 billion in healthcare spending during the coming decade. While generic chemical compounds like Norvasc and Metoprolol usually sell for less than 20% the cost of the brand product, biosimilars are expected to sell for 60% to 80% of the cost of branded biologics. The difficulty of producing and gaining approval for biosimilars will provide manufacturers increased pricing power and larger margins compared to traditional generic medications.

Biosimilars represent a tremendous opportunity for pharma and biotech companies that can successfully manufacture and market them. The global market for biosimilars will range between $11 billion and $25 billion by 2020, accounting for 4 to 10 percent of the total market for biotech drugs, according to IMS Health. Despite the potential hurdles to both interchangeability and exclusivity, patent expiries in the next two years put around $11 billion in biologic drug sales into play. That kind of potential along with the establishment of a designated approval pathway clears away some lingering doubts about the viability of generic competition.

As for the industry, potential biosimilar manufacturers continue to make deals. While there are no currently marketed biosimilars in the U.S., so-called innovator companies including Amgen, Pfizer, Novartis, and Eli Lilly have joined the ranks of generic firms such as Teva in developing biosimilars. Amgen told GEN that as a leading provider of high-quality biologic medicines, it understands the challenges of developing and manufacturing innovative and biosimilar medicines and appreciates the agency’s efforts on the guidelines, and encourages adoption of a thorough review and approval process.

While it remains to be seen whether approved biosimilars provide the savings in healthcare costs that the Congressional Budget Office optimistically predicted, both the FDA and the industry are moving toward making them a reality in the U.S. As per the three dozen or so requests for meetings, FDA staffers are holding pre-IND meetings with sponsors and encouraging all prospective biosimilar makers to seek early advice. Nine INDs for biosimilar have been filed so far, and the agency is anticipating a full 351(k) application soon.

http://www.genengnews.com/insight-and-intelligenceand153/what-will-fda-biosimilars-guidelines-mean-for-industry/77899555/

More than a year after launching a dialogue with industry regarding biosimilars, FDA is holding a morning-long public meeting today. The proposed approval pathway and fees drug developers must pay for the five fiscal years starting October 1, 2012, will be discussed. The agency is soliciting public comment through January 6, 2012

Those comments are expected to shape a final FDA recommendation on biosimilar user fees, which the agency plans to send to Congress by January 15, 2012. On December 7, the agency published “Biosimilar Biological Product Authorization Performance Goals and Procedures, Fiscal Years 2013 through 2017.”

The user fee program is expected to aid FDA in developing the final abbreviated approval pathway for biosimilars, which was required under the Biologics Price Competition and Innovation Act (BPCIA) of 2009. BPCIA was tucked into page 686 of the Patient Protection and Affordable Care Act enacted last year by President Obama. Janet Woodcock, M.D., director of FDA’s Center for Drug Evaluation and Research co-authored a paper published this August in The New England Journal of Medicine that provided some clues on the overall approval pathway.

http://www.genengnews.com/insight-and-intelligenceand153/fda-holds-public-discussion-of-user-fee-program-for-biosimilars/77899515/

The initial fee would be 10% of the fee established for a drug application under PDUFA each year from FY 2013 through 2017. The agency would collect only one initial BPD fee per product, regardless of the number of proposed indications.

Sponsors that submit marketing applications would pay fees equal to those established for drug applications under PDUFA minus the cumulative amount of BPD fees. Under PDUFA, 2012 fees for drug products go up as high as $1.84 million.

“By providing FDA with these resources, they would be able to meet with sponsors, provide clear and established guidelines for regulatory action, and as a result that should reduce the barriers to market entry even more than what would be represented through a modest fee like this,” Emmett said. Since established biopharma companies are more likely to produce biosimilars than early-stage companies, “I wouldn’t anticipate that $180,000 would be a significant barrier to market,” Emmett added.

“FDA anticipates a modest level of funding from these sources initially because only biosimilar biological products that are approved for marketing would be subject to these fees,” the agency said.

http://www.genengnews.com/insight-and-intelligenceand153/fda-holds-public-discussion-of-user-fee-program-for-biosimilars/77899515/

Biosimilars and Follow-On Branded Biologics

Promoting Innovation and Access to Life-Saving Medicine Act (H.R.1427, a bill from the first session of the 111th Congress) and the FTC’s report titled Emerging Health Care Issues: Follow-on Biologic Drug Competition are intended to provide the rationale for moving access to biosimilars/follow-on biologics and driving the legislative compromise. Of particular interest is the FTC’s projection of what cost savings (10–30%) will actually be achieved, and that the originator biologic manufacturer may likely retain 90% of its market.

When a new human growth hormone (hGH) product tried to compete with Genentech’s hGH, physicians hesitated to move patients on to it, so its market was just new patients. If there is only a 10–30% price differential for biosimilar/follow-on biologics and they lack an AB substitutability rating, one would anticipate the same reluctance to switch patients.

http://www.genengnews.com/gen-articles/biosimilars-and-follow-on-branded-biologics/2981/?page=2

FDA’s draft guidance for biosimilars drew mostly good marks from industry at the hearing held May 11. Executives from a dozen biopharma companies, however, pressed for greater flexibility in the definition of proteins, tighter standards in naming and labeling follow-on biologics, as well as more details on moving drugs through agency approvals.

Draft Guidance for Industry and FDA Staff: Technical Considerations for Pen, Jet and Related Injectors Intended for Use with Drugs and Biological Products, April 2009.) The Guidance recognizes that these are innovative approaches to deliver drugs or biologics products that may enhance accuracy and patient compliance.

One major significant issue of this Guidance lies in its application to biosimilars, facilitating their conversion into higher-value follow-on branded products. As an example, Novo Nordisk is now introducing its next-generation FlexPen, a prefilled insulin delivery device that the company reports has a 25–41% lower force than the existing SoloStar and KwikPen devices; diabetic patients prefer lower-force insulin injections since they are less painful.

After obtaining FDA approval to market in the U.S., a first-generation biologic may have little commercial value as a commodity product and have a BX rating (not substitutable), since most biopharma companies have developed a second- or third-generation biologic with an innovative delivery system—a specialty product. It is anticipated that specialty products will command prices near or only 10–20% less than that of the originator product, even though they will not have a BX rating. In this scenario, the initial approval of the first-generation biosimilar is really a strategy to rapidly enter the marketplace, then quickly evolve into a higher-value specialty, often called a follow-on branded product.

http://www.genengnews.com/gen-articles/biosimilars-and-follow-on-branded-biologics/2981/

CMC Issues and Regulatory Requirements for Biosimilars

Dr. Bao-Lu has exposed very important CMC Issues and Regulatory Requirements for Biosimilars in

http://www.tbiweb.org/tbi/file_dir/TBI2009/Bao-lu%20Chen.pdf

Chemistry, Manufacturing and Controls (CMC), preclinical and clinical are three critical pieces in biosimilars development. Unlike a small-molecule generic drug, which is approved based on “sameness” to the innovator’s drug; a biosimilar is approved based on high similarity to the original approved biologic drug. This is because biologics are large and complex molecules. Many functional-, safety- and efficacy-related characteristics of a biologic depend on its manufacturing process. A biosimilars manufacturer won’t be able to exactly replicate the innovator’s process. The traditional abbreviated pathway for generic drug approval through the Hatch- Waxman Act of 1984 doesn’t apply for biosimilars as drugs and biologics are regulated under different laws. New laws and regulations are needed for biosimilars approval in the US. The EU has issued biosimilars guidelines based on comparative testing against the reference biologic drug (the original approved biologic). A full scale CMC development is required including expression system, culture, purification, formulation, analytics and packaging. The manufacturing process needs to be developed and optimized using state-of-the-art technologies. Minor differences in structure and impurity profiles are acceptable but should be justified. Abbreviated clinical testing is required to evaluate surrogate markers for efficacy and demonstrate no immunogenic response to the product.

We anticipate the package for a biosimilars approval in the US will be similar to that in the EU and contain a full quality dossier with a comparability program including detailed product characterization comparison and reduced preclinical and clinical requirements.

Biosimilars Become Inevitable

Biologics developed through biotechnology constitute an essential part of the pipeline for medicines available to patients today. Biologic drugs are quite expensive and many of them are top-selling medicines (see Table 1). Since they come at extremely high prices to consumers, some patients may not be able to afford the use of biologics as the best-available treatments to their conditions. The patent protection on a large number of biologics has expired since 2001. These off-patent biologics include Neupogen, Novolin, Protropin, Activase, Epogen or Procrit, Nutropin, Humatrope, Avonex, Intron A, and Humulin. Traditionally, when a drug patent expires, a generic drug will be quickly developed and marketed. Similarly, generic version of off-patent biologic drugs (also referred to biosimilars or follow-on biologics or biogenerics) represents an extraordinary opportunity to companies that want to seize the potentially great commercial rewards in this unexploited territory. Biosimilars not only benefit the biosimilar manufacturers but also can save patients, and insurance companies, substantial cost and allow patients to gain access to more affordable biologics resulting in market expansion. The government can use biosimilars to reduce healthcare costs. Therefore, development and marketing of bosimilars are supported by both manufacturers and consumers.

Differences between Generic Drugs and Biosimilars

Enacted in 1984, the US Drug Price Competition and Patent Term Restoration Act, informally known as the “Hatch-Waxman Act of 1984” standardized US procedures for an abbreviated pathway for the approval of small-molecule generic drugs. The generic drug approval

is based on “sameness”. In comparison to the innovator’s drug, a generic drug is a product that has the same active ingredient, identical in dose, strength, route of administration, safety, efficacy, and intended use. For approval, the generic companies can go through the Abbreviated

New Drug Application (ANDA) process with reduced requirement in comparison to approval for a new drug entity. The generic drugs need to show bioequivalence to the innovator drugs typically based on pharmacokinetic parameters such as the rate of absorption or bioavailability in 24 to 36 healthy volunteers. No large clinical trials for safety and efficacy are required. The generic companies can rely on the FDA’s previous findings of safety and effectiveness of the innovator’s drugs.

However, the abbreviated pathway for generic drugs legally doesn’t apply to biologics as small-molecule drugs and biologics are regulated under different laws and approved through different pathways in the US (Table 2). Small-molecule drugs are regulated under the Food, Drug and Cosmetic Act (FD&C) and require submission of a New Drug Application (NDA) to FDA for drug review and approval. Biologics are regulated under the Public Health Service Act (PHS) and require submission of a Biologic License Application (BLA) to FDA for review and approval. The Hatch-Waxman Act of 1984 doesn’t apply for biosimilars. New laws are needed to establish a pathway for biosimilar approval.

There are some crucial differences between biologics and small-molecule drugs. Small-molecule drugs are made from chemical synthesis. They are not sensitive to process changes. The final product of a small-molecule drug can be fully characterized. The developmentand production of generic drugs are relatively straightforward. Biologics are made from living organisms so that its functional-, efficacy- and safety-related properties depend on its manufacturing and processing conditions. They are sensitive to process changes. Even minor modifications of the manufacturing process can cause variations in important properties of a biological product. Thus it is believed that a biologic product is defined by its manufacturing process. Biologics are 100- or 1,000-fold larger than small-molecule drugs, possess sophisticated three-dimensional structures, and contain mixtures of protein isoforms. A biological product is a heterogeneous mixture and the current analytical methods cannot characterize these complex molecules sufficiently to confirm structural equivalence with the reference biologics.

Laws and Regulatory Pathways for Drug Approval in the US

Law/Application Small-molecule Drug Biologics

Law Food, Drug and Cosmetic Act (FD&C) Public Health Service Act (PHS)

Drug application New Drug Application (NDA) Biologic License Application (BLA)

Generic application Abbreviated New Drug Application(ANDA) NEW pathways beyond BPCIA, 2009

Differences between small-molecule drugs and biologics

Product characteristics

Small-molecule generics Small, simple molecule

(Molecular weight: 100-1,000 Da)

Biosimilars Large, complex molecules, Higher order structures, Post-translational, modifications

(Molecular weight: 15,000-150,000 Da)

Production

Small-molecule generics Produced by chemical synthesis

Biosimilars Produced in living organisms

Analytical testing

Small-molecule Well-defined chemical structure, all its various components in the finished drug can be determined

Biosimilars Heterogeneous mixture, difficult to characterize, some of the components of a finished biologic may be unknown

Process dependence

Small-molecule Not sensitive to manufacturing process changes. The finished product can be analyzed to establish the sameness.

Biosimilars Sensitive to minor changes in manufacturing process. The product is defined by the process

Identity and purity

Small-molecule Often meeting pharmacopeia or other standards of identity (e.g., minimums for purity and potency)

Biosimilars Most have no pharmacopeia monographs

immunogenicity issues prior to 1998. When J&J made a change in the Eprex formulation by replacing human serum albumin (HAS) with polysobate 80 and glycine in response to the

request from European health authorities, some patients developed pure red-cell aplasia (PRCA), a severe form of anemia. Eprex induced antibodies neutralize all the exogenous rHuEPO and cross-react with endogenous erythropoietic proteins. As a result, serum EPO is undetectable

and erythropoiesis becomes ineffective. Upon investigation, J&J found that polysorbate 80 might have caused uncoated rubber stoppers in single-use Eprex syringes to leach plasticizers, which stimulated an immune response that resulted in PRCA. Replacing with Teflon coated stoppers resulted in 90% decrease in PRCA by 2003 [3,4]. The effect of neutralizing antibodies has not always resulted in serious clinical consequences. Three interferon beta products, Betaseron, Rebif and Avonex, are marketed by three different companies. These products induce neutralizing antibodies in multiple sclerosis patients from 5 to 50% after one year treatment. Although these antibodies might be associated with loss of efficacy of treatment resulting in some patients to withdraw from the treatment, it seems no other severe adverse effects were detected [5,6].

Regulatory Landscape

The US, the EU and Japan are the three cornerstonemembers of the International Conference on Harmonization (ICH), which intends to harmonize the regulatory requirements for drug or biologic approval in these three regions. With the other two members, the EU and Japan, already have established biosimilar approval procedures (see below), the US lags behind in the biosimilar race. There are no formal approval pathways for biosimilars in the US. Congress needs to establish a legal framework in order for FDA to develop guidelines. Legislation has been under discussion in Congress since 2007. The legislative debate is centered on patient safety and preserving incentives to innovate with introduction of biosimilars. Two bills introduced in March 2009 deserve attentions [7,8]. The Waxman bill (H.R. 1427) proposes 5 years of market exclusivity to the innovator companies and requires no clinical trials for biosimilar development. The Eshoo bill (H.R. 1548) proposes 12 years of market exclusivity to the innovator companies and requires clinical trials for biosimilar development. Obama administration appears to favor a 7-year market exclusivity [9]. Once a legal framework is established for biosimilars, the FDA will likely take a conservative approach using the comparability as an approval principle. Clinical proof of efficacy and safety will be required, probably in reduced scale.

In the EU, the European Medicines Agency (EMEA) issued regulatory guidelines for approving biosimilars in 2005 (Figure 1) [10-16]. These include two general guidelines for quality issues [11] and non-clinical and clinical issues [12] and four class-specific annexes for specific data requirements for Granulocyte-Colony Stimulating factor (G-CSF) [13], Insulin [14], Growth hormone [15] and Erythropoietin [16]. In addition, a concept paper on interferon alpha [17] is also available. So far, there are eleven biosimilar products which received market authorization in the EU and they are biosimilar versions of human growth hormone, Epoetin and filgrastim. It is estimated six to eight years on average for a biosimilar to be developed [18].

The EMEA treats a biosimilar medicine as a medicine which is similar to a biological medicine that has already been authorized (the “biological reference medicine”) in the EU, The active substance of a biosimilar medicine is similar to the one of the biological reference medicine.

A biosimilar and the biological reference medicine are used in general at the same dose to treat the same disease. A biosimilar and the biological reference medicine are not automatically interchangeable because biosimilar and biological reference medicine are only similar but not identical. A physician or a qualified healthcare professional should make the decision to treat a patient with a reference or a biosimilar medicine. Since the biosimilar may contain different inactive ingredients, the name, appearance and packaging of a biosimilar medicine differ to those of the biological reference medicine. In addition, a pharmacovigilance plan must be in place for post-marketing safety monitoring.

Japan’s Ministry of Health, Labor and Welfare (MHLW) issued guidelines for follow-on proteins or biosimilars approval in March 2009. The first biosimilar, Sandoz’ growth hormone Somatropin, was approved in June 2009. The MHLW’s guidelines consider biosimilars drugs which are equivalent and homogeneous to the original biopharmaceuticals in terms of quality, efficacy and safety. Biosimilars are also requested to be developed with updated technologies and knowledge. Biosimilars need to demonstrate enough similarity to guarantee the safety and efficacy instead of absolute identity to the original biologics. Biosimilars’ regulatory approval applications will be categorized separately from conventional generic drugs. In general, the applications should be submitted, as the new drug applications, with data from clinical trials, manufacturing methods, long-term stability and information on overseas use. The MHLW will assess the data on absorption, distribution, metabolism and excretion (ADME) on a case-by-case basis. The applications do not need to provide data on accessory pharmacology, safety pharmacology and genotoxicity.

Biosmilars are already thriving in Eastern Europe and Asia, where regulatory and intellectual property (IP) standards for biosimilars are more liberal. Biosimilars developed in these regions are primarily sold domestically. These markets are considered less controlled. The quality of the biosimilars may not be in full compliance with ICH guidelines although they are often developed through comparative quality testing and clinical trials against the biologics which are already approved in Western countries

Comparability Demonstration

A comparability exercise based on the ICH guideline [22] needs to be performed to demonstrate that the biosimilar product and the reference biologic product have similar profiles with respect to product quality, safety, and efficacy. This is accomplished by comparative testing of the biosimilar product and the reference biologic product to demonstrate they have comparable molecular structure, in vitro and in vivo biological activities, pre-clinical safety and pharmacokinetics, and safety and efficacy in human patients. Comparison of quality attributes between the biosimilar and the reference biologic product employs physicochemical and biological characterization. Comparability on physical properties, amino acid sequence, high order structures, post-translationally modified forms are evaluated by physicochemical tests. In vitro receptor-binding or cell-based (binding) assays or even the in vivo potency studies in animals need to be performed to demonstrate comparable activity despite they are often imprecise. Levels of product related impurities (aggregates, oxidized forms, deamidated forms) and process related impurities and contaminants (host cell proteins, residual genomic DNA, reagents, downstream impurities) need to be assessed and quantified. Stability profiles of the biosimilar product and the reference biologic product also need to be studies by placing the products under stressed conditions. The rate of degradation and degradation profiles (oxidation, deamidation, aggregation and other degradation reactions) will be compared. If unknown degradation species are detected, they need to be studied to determine if they affect safety and efficacy. If differences on product purities and stability profiles are present between the biosimilar product and the reference biologic product, these differences need to be justified using scientific knowledge or preclinical or clinical studies. Changes in the impurity profile should be justified as well.

The demonstration of comparability in quality attributes does not necessarily mean that the biosimilars and the reference biologics are identical, but that they are highly similar. In many cases, the relationship between specific quality attributes and safety and efficacy has not been fully established. For example, physicochemical characterization cannot easily predict immunogenicity and slight changes in manufacturing processes or product composition can give rise to unpredicted changes in safety and efficacy. Changes in bioavailability, pharmacokinetics, bioactivity bioactivity, and immunogenicity are the main risks associated with the manufacturing of biosimilars. In vivo studies should be designed to measure the pharmacokinetics and pharmacodynamics relevant to clinical studies. Such in vivo studies should be designed to detect response differences between the biosimilar and the reference biologic not just responses per se. In vivo studies of the biosimilar’s safety in animals may be used to research any concerns into the safety of the biosimilar in human patients. Although extensive clinical testing is not necessary for biosimilars, some degree of clinical testing is needed to establish therapeutic comparability on efficacy and safety between the biosimilar and the reference biologic product [23,24]. This includes using surrogate markers of specific biologic activity as endpoints for demonstrating efficacy, and showing that patients didn’t develop immunogenic responses to the product. In general, the approval of biosimilars will be based on the demonstration of comparable efficacy and safety to an innovator reference product in a relevant patient population. Clinical data requirement for each individual product will be different and will be determined on a case-by-case basis.

Small-molecule Generics versus Biosimilars

Small-molecule

Approval based on “sameness”

Biosimilars

Approval based on “high similarity”

Small-molecule

Replicate the innovator’s process and product and perform a bioavailability study demonstrating similar pharmacokinetic properties

Biosimilars

Full CMC development with comparative testing, conduct substantial clinical trials for efficacy and safety including immunogenicity

Small-molecule

Abbreviated registration procedures in Europe and US

Biosimilars

Regulatory pathway is defined in EU on “Comparability” status, no pathway yet in US under BLA

Small-molecule

Therapeutically equivalent, thus interchangeable

Biosimilars

Lack of automatic substitutability

Small-molecule

$1 to $5 million to develop

Biosimilars

$100-$200 million to develop

Small-molecule

Brand-to-generic competition

Biosimilars

Brand-to-Brand competition

Conclusion

The patent provisions of the Biosimilar Act, 2009 establish demanding and time-sensitive disclosure requirements. ObamaCare upheld by the Supreme Court is a victory for future development of pathways for biosimilar regulatory approval and eventually biosimilar generic drugs.

Biosimilars are defined as biological products similar, but not identical, to the reference biological products that are submitted for separate marketing approval following patent expiration of the reference biological products. As one of the ICH members, the US needs to catch up with the EU and Japan as those two countries have already issued regulatory guidelines for biosimilars. 2009 and 2012 represent milestones in the regulatory provisions for biosimilars in the US.

Once Congress establishes a legal framework, FDA is expected to set up a biosimilar approval pathway which will be similar to those in the EU and Japan and harmonized under ICH. The biosimilar will need a full CMC development package plus demonstration of comparable quality attributes and comparable efficacy and safety to the innovator’s product. Table 5 provides a comparison summary between small-molecule generics and biosimilars. It will take a much bigger effort to develop a biosimilar than a generic drug. Automatic substitution between the innovator product and a biosimilar is not appropriate as a biosimilar is not a generic version of the innovator product and is approved based on comparability to the innovator product.

REFERENCES

1. Federal Trade Commission Report, June 2009.

2. Schellekens, H.; Nat. Rev. Drug Discov. 2002, 1: 457-462.

3. Van Regenmortel, M.H.V.; Boven, K. and F. Bader, BioPharm International, August 1, 2005, Vol 18, Issue 8.

4. Locatelli, F.; Del Vecchio, L. and P. Pozzoni, Peritoneal Dialysis International, 2007, 27(Supplement 2): S303-S307.

5. Hartung, H.P.; Munschauer, F. And Schellekens, H., Eur J. Neurol., 2005, 12, 588-601.

6. Malucchi, S. et al., Neurol. Sci., 2005, 26, suppl, 4:S213-S214.

7. Greb, E., Pharmaceutical technology, June 2009, pp. 36-42.

8. Del Buono, B.J., BioPharm International, July 2009, pp 46-53.

9. Usdin, S., Biocentury, July 20, 2009, 17(32): A1-A6.

10. “Guideline on Similar Biological Medicinal Products”, (Doc. Ref.: EMEA/CHMP/437/04, London, 30 October 2005).

11. “Guideline on Similar Biological Medicinal Products Containing Biotechnology-derived Proteins as Active Substance: Quality Issues”, (Doc. Ref.: EMEA/ CHMP/BWP/49348/2005, London, 22 February 2006).

12. “Guideline on Similar Biological Medicinal Products Containing Biotechnology-derived Proteins as Active Substance: Non-Clinical and Clinical Issues”, (Doc. Ref.: EMEA/CHMP/BMWP/42832/2005, London, 22 February 2006).

13. “Annex to Guideline on Similar Biological Medicinal Products Containing Biotechnology-derived Proteins as Active Substance: Non-Clinical and Clinical Issues – Guidance on Similar Medicinal Products Containing Recombinant Granulocyte-Colony Stimulating Factor”, (Doc. Ref.: EMEA/CHMP/ BMWP/31329/2005, London, 22 February 2006).

14. “Annex to Guideline on Similar Biological Medicinal Products Containing Biotechnology-derived Proteins as Active Substance: Non-Clinical and Clinical Issues – Guidance on Similar Medicinal Products Containing Recombinant Human Soluble Insulin”,(Doc. Ref.: EMEA/CHMP/BMWP/32775/2005, London, 22 February 2006).

15. “Annex to Guideline on Similar Biological Medicinal Products Containing Biotechnology-derived Proteins as Active Substance: Non-Clinical and Clinical Issues – Guidance on Similar Medicinal Products Containing Somatropin”, (Doc. Ref.: EMEA/ CHMP/BMWP/94528/2005, London, 22 February 2006).

16. “Annex to Guideline on Similar Biological Medicinal Products Containing Biotechnology-derived Proteins as Active Substance: Non-Clinical and Clinical Issues – Guidance on Similar Medicinal Products Containing Recombinant Erythropoietins”, (Doc. Ref.: EMEA/CHMP/BMWP/94526/2005 Corr., London, 22 February 2006).

17. “Annex to Guideline on Similar Biological Medicinal Products Containing Biotechnology-derived Proteins as Active Substance: (Non) Clinical Issues – Concept paper on similar biological medicinal products containing recombinant alpha-interfero (Doc. Ref.: CHMP/BMWP/7241/2006, London, 26 April 2006).

18. “EGA Handbook on Biosimilar Medicines”, European Generic Medicines Association, Received August 2009).

19. “Points to Consider in the Characterization of Cell Lines to Produce Biologicals”, FDA CBER, 1993.

20. Chirino, A.J. and A. Mire-Sluis, Nature Biotechnology, 2004, 22(11): 1383-1391.

21. Kendrick, B.S. et al., BioPharm International, 2009, August, pp 32-44.

22. “Comparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process”, ICH Harmonized Tripartite Guideline Q5E, 18 November 2004.

23. Mellstedt, H.; Niederwieser, D. and H. Ludwig, Annals of Oncology, September 14, 2007, pp. 1-9.

24 Schellekens, H., NDT Plus, 2009, 2 [suppl 1]: i27- i36.

http://www.wolfgreenfield.com/files/2426_biosimilars_2_final_pdf.pdf

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The role of biomarkers in the diagnosis of sepsis and patient management

Posted in Biomarkers & Medical Diagnostics, Chemical Biology and its relations to Metabolic Disease, Computational Biology/Systems and Bioinformatics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Health Economics and Outcomes Research, Infectious Disease & New Antibiotic Targets, Metabolomics, Population Health Management, Genetics & Pharmaceutical, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Statistical Methods for Research Evaluation, Systemic Inflammatory Response Related Disorders, tagged health, Intensive care unit, Sepsis shock, Systemic inflammatory response syndrome, Transthyretin (TTR) on July 28, 2012| 8 Comments »

The role of biomarkers in the diagnosis of sepsis and patient management

Author: L. H. Bernstein, MD, FCAP

Key words: Systemic Inflammatory Response Syndrome (SIRS), sepsis, septic shock, mean arterial blood pressure (MAP), procalcitonin, combinatorial analysis, effect size

Highlights:
1. The systemic inflammatory response syndrome (SIRS) is an acute response to trauma, burn, or infectious injury characterized by fever, hemodynamic and respiratory changes, and metabolic changes, not all of which are consistently present.

2. The SIRS reaction involves hormonally driven changes in liver glycogen reserves, triggering of lipolysis, lean body proteolysis, and reprioritization of hepatic protein synthesis with up-regulation of synthesis of acute phase proteins and down-regulation of albumin and important circulating transport proteins.

3. Understanding of the processes leads to the identification of biomarkers for identification of sepsis and severe, moderate or early SIRS, which also can hasten treatment and recovery.

4. The SIRS reaction unabated leads to a recurring cycle with hemodynamic collapse from septic shock, indistinguishable from cardiogenic shock, and death.

Abbreviations: Systemic Inflammatory Response Syndrome (SIRS), procalcitonin (PCT), C-reactive protein (CRP), mean arterial blood pressure (MAP), Intensive care unit (ICU), total white blood cell count (WBC), transthyretin(TTR)

Summary
By focusing on early and accurate diagnosis of infection in patients suspected of SIRS antibiotic overuse and its associated morbidity and mortality may be avoided, and therapeutic targets may be identified. This discussion investigates the performance of diagnostic algorithms and biomarkers for sepsis in patients presenting with leukocytosis and other findings. Suspected patients are usually identified by WBC above 12,000/mL PCT level , SIRS and other criteria, such as serum biomarkers of sepsis. In this writer’s study of 435 patients, procalcitonin alone was a superior marker for sepsis. In patients with sepsis there was a marked increase in PCT (p = 0.0001). PCT was increased in patients requiring ICU admission, heart rate and blood pressure monitoring, and assisted ventilation.(p = 0.0001). Means for SIRS/non-SIRS were: CRP 802/404 mg/L; PCT 20.6/7.5 ng/mL; TTR 87.8/125 mg/L. A comprehensive overview of at least a decade of work is provided.

Introduction

Sepsis is a costly diagnosis in hospitalized patients and carries a high financial risk as a comorbidity and a payment penalty for failure to diagnose in a timely manner (1-4) under the severity of illness CMS reimbursement guidelines as a patient safety hazard, with pneumonia and sepsis among the ten most costly among hospital admissions. A polypeptide identical to a prohormone of calcitonin, procalcitonin, was initially described as a potential marker of bacterial disease by Assicot et al.(5). Procalcitonin is almost undetectable under physiological conditions (pg/ml range), but rises to very high values in response to bacteraemia or fungaemia, and appears to be related to the severity of infection.(6) Sequential measurements in patients with bacteraemia have shown a rapid fall within 48 hours of antibiotic administration.

Is it an unlikely candidate sepsis biomarker? It is a precursor of calcitonin, and under ordinary circumstances can be accounted for by its production in the thyroid. It is widely produced extrathyroidally with sepsis. The main reason for such interest is the response seems to be uncoupled to the systemic inflammatory response, as CRP is. What is it a response to? What is the role it has in primary cellular immune response? There is no question that it is found in very low level without serious infection, so that a low level would remove the necessity for a blood culture. In other words it predicts absence of sepsis. Is it fortuitous or serendipity?

On the other hand, we now refer to bacterial and abacterial sepsis. So there are a significant proportion of sepsis diagnoses for which cultures are negative. You might decide that the method of taking cultures x3 at different times and from different sites (not universally practiced) might account for the negative cultures. It was reported in the New York Times a week ago that a child came to the emergency room in a NY hospital with a simple sports injury abrasing the skin surface, was sent home, returned, and died in 24 hours. It’s not such an easy call, despite the result.

There have been numerous studies of the early recognition of sepsis and related diseases in patients related to admission and intensive care. The consensus guideline has used a SIRS criteria (7, 8). The SIRS criteria (7,8) include temperature ^o C. >= 38^o C., heart rate > 90 beats per minute, respiratory rate >20 breaths per minute or PaCO₂ < 32 mm of Hg, WBC > 12,000/mL or < 4,000/mL, or > 10% band forms. For the diagnosis of sepsis (2 or more SIRS criteria and confirmed or suspected infection) the SIRS criteria are insufficient with a very high false positive rate, so that there are medical institutions that require three. The observation of fever, tachypnea, and tachycardia may well not be present early, and the observation of leukocytosis with or without band neutrophilia are unreliable. The use of a plasma lactic acid measurement has been added, but it is basically a reflection of decreased splanchnic circulation to the superior mesenteric artery and liver bed. A better case has been made for absolute neutophilia (9), with an adjustment for high lymphocyte counts in children in the first six months, and for the identification of increased immature myeloid precursors (myelocytes and metamyelocytes). The C-reactive protein, a long established acute phase protein, is not predictive at levels under 520 mg/L because it is elevated in a variety of chronic inflammatory conditions. Moreover, it is infrequently used in adult medical practice for that reason, except for the high sensitivity CRP, which has been shown to be relevant to treatment of coronary heart disease by the Jupiter study (10), but also has raised the question of overuse of the statins with the undesirable side effect of skeletal muscle loss. We can explore the validity of over ten years of studies in Europe and US, showing a debated benefit from using the procalcitonin biomarker (PCT, Brahms)(11-28).

The question arises whether there is a difference in PCT response between Gm- and Gm+, and there is, but it doesn’t matter. We can’t be certain that this reaction is produced by vascular endothelium. I could identify at least one case where I knew the patient had no culture taken and died in cardiovascular shock. At that stage of decompensation what would make one think that it was other than pump failure? But in the evolution of cardiogenic shock, the perfusion of the superior mesentery artery could well be decompensated with the release of bacteria of intestinal organs. Quite a bit of work has been done in surgical research that indicates that there is bacterial migration to regional nodes, but it isn’t problematic unless there is a systemic insult.

Then there needs to be an explanation of events related to gene regulation and cell signaling, that is a blank screen. The cost of the test has been a factor limiting the use, which I think is not the key issue.

Results

A multivariable study with 435 patients to determine whether procalcitonin alone is a superior marker for sepsis established a difference between patients with and without sepsis , as the increase in PCT with sepsis was significant at p = 0.0001. The PCT was also increased in patients who were admitted to the ICU, requiring assisted ventilation and monitoring of heart rate and blood pressure, significant at p = 0.0001. The highest values occur in septic shock, even though mild elevations are seen with localized infection. A PCT level distinguishes between four subgroups of the population: no infection, local infection, sepsis, and severe sepsis and septic shock. The PCT is very low with no infection and rises to levels above 5 with moderate to severe sepsis. Table 1 compares the selected biomarker results for patients in ICU and not in ICU by the t test with adjustment for unequal variances. The salient points are noted. PCT, not CRP, is significant for a difference between SIRS positive and SIRS negative patients in ICU (p=0.0001 vs 0.166), with a mean CRP of 495 mg/L in non ICU patients. The result is expected because the CRP is elevated in other conditions without sepsis, and the patients in the ICU and outside the ICU may have a variety of inflammatory conditions. There is a difference in PCT between ICU and non-ICU patients without SIRS (p = 0.0001), indicating that PCT is identifying infection, if not sepsis, in this cohort of patients. Patients in the ICU with SIRS (vs without) have a mean PCT of 35.2 vs 3.7 ng/ml, a clinically as well as statistically significant increase in PCT (Mann-Whitney, p = 0.0001). On the other hand, patients without SIRS in the ICU also have higher CRP [1] and PCT [2] than those not in ICU (1, p = 0.032; 2, p = 0.004), but the CRP difference just reaches statistical significance while the unexpected PCT increase is a big effect. The means obtained for SIRS/non-SIRS are: CRP [1] 802/404 mg/L; PCT [2] 20.6/7.5 ng/ml; TTR [3] 87.8/125 mg/L. So we see an increase of CRP and PCT with SIRS, as expected, and a decrease in TTR to below 100 mg/L as an obligatory response in relationship to the severity of the inflammatory state. The patients with SIRS and those with sepsis, respectively, had significant elevations of CRP [1] and PCT[2], and decrease of TTR[3] by Mann-Whitney test (SIRS, p = 0.006, CRP [1]; 0.0001, PCT [2]; 0.0001 TTR[3]; sepsis, p = 0.010, CRP [1]; 0.014, PCT [2]; 0.004, TTR [3]).

Finally, we are particularly interested in combinations of variables for predicting infection and the stage of infection using PCT, MAP (mean arterial blood pressure), WBC. The model fit looks good based on the chi-squared statistics. The relationship between the predictor variables and SIRS or ICU is consistent with the large increases of PCT described. In exploring this strong association between the chosen predictors for SIRS and ICU – PCT, WBC, MAP and TTR (CRP not used) demonstrated that each can be used in a classification matrix. (Table 2) One might create a 4-letter code using M (MAP)_T (TTR)_W (WBC)_S (SIRS) to test for PCT effectiveness in the same way that one would test PCT against the clinical diagnosis of sepsis, but excluding the variable that we are interested in proving. PCT can then be added as the fifth variable. The data was classified according to mean arterial blood pressure (MAP), TTR, white cell count (WBC), and SIRS as described and the PCT was kept out of the classification. The PCT, MAP and SIRS differences were all significant at 0.0001, and the TTR had a p = 0.021 in the Kruskall Wallis analysis by ranks. A similar, but simpler classification did not include either PCT or MAP, resulting in three classes. The PCT increased within the subgroups of WTSIRS (2.5, 25, 50, 75 and 97.5 percentiles. Further, the subgroup of patients classified by MAP, TTR, WBC and SIRS, had a dramatic decline in the MAP by subclass, the last of which is comparable to septic shock. We constructed a latent class model using the ordinals of PCT, MAP and WBC scaled to intervals. The combinatorial classes formed by the predictors have a defined contribution (percent) of each predictor. The R², L² and C² are shown.

Degrees of freedom (df) 282 p-value

L-squared (L²) 217.6904 1.00

X-squared 235.4391 0.98

Cressie-Read 209.1484 1.00

^aBIC (based on LL) 634.1041

^bAIC (based on LL) 494.7921

^aBayes Information Criterion, ^bAkaike’s Information Criterion

Model for Dependent

R²

Class1 0.7961

Class2 0.9136

Class3 0.9782

Class4 0.6410

Overall 0.9319

Chi-squared Statistics

Degrees of freedom (df) 258 p-value

L-squared (L²) 248.9633 0.65

X-squared 230.6279 0.89

Cressie-Read 222.0675 0.95

BIC (based on L²) -1238.4560

AIC (based on L²) -267.0367

Even though CRP has validity for identifying SIRS in our exploratory study, the specificity and its usefulness at a cutoff at 52 mg/dL raised significant concerns with respect to with respect to distinguishing SIRS with and without infection. Keep in mind that large variances in CRP exist between the subgroups, which is problematic because of the CRP elevation in patients with metabolic syndrome and with chronic inflammatory diseases, but not necessarily sepsis. TTR is also decreased, as CRP is elevated, in patients with inflammatory conditions without sepsis.

The data demonstrated a clear relationship between high PCT and both SIRS and the ICU placement of the patient. We also showed the elevation of PCT in concert with severity of infection, as determined by medical record review. Patients with sepsis are transferred to the ICU for management. These patients are on antibiotics and they are monitored for drop in mean arterial blood pressure over the first 72 hours, as a drop in MAP below 72 indicates septic shock. The progression from SIRS to septic shock goes from single organ (lung, kidney) to double organ, to multiple organ dysfunction syndrome is accompanied by increased lactic acid, tachycardia, decreased MAP, and finally, increase in serum bilirubin. We would expect and find elevations of PCT with pneumonia, deep wounds, and pyelonephritis as well as sepsis, but these patients would be expected to meet the SIRS criteria. Our study was not designed to demonstrate how PCT might detect sepsis in older patients with negative SIRS criteria in the ICU who are on ventilator assistance and who may not develop a febrile response. One has to consider that this is related to PCT elevation being partly independent of the SIRS response.

We then showed the same relationship to biomarker combinations that classify the data in accordance with the severity of infection. The WBC count is the weakest classification variable, but it is in the SIRS criteria and it is of greatest value with a finding of immature neutrophils. However, the band count is now considered part of the mature neutrophil count so that the absolute neutrophil count and the immature granulocytes measured by flow cytometry (myelocytes and metamyelocytes) are superior to the tWBC and bands ( ). The MAP is valuable for identifying the patients at highest risk of circulatory collapse with a drop in the MAP and transfer to ICU (on pressors). The drop in MAP within 72 hours is important for making decisions about Activated protein C (Xygris), which is a critical decision. APC has been removed from the market. We included the TTR, which decreases in patients with SIRS in proportion to the severity of illness. If we compare these predictors in patients with a diagnosis of sepsis, CRP, PCT (and TTR) all have significant differences between ICU and not ICU admission at p < 0.05. The elevation of white cell count and percent neutrophils, unexpectedly has no separatory power. This would not be the case for a postoperative patient who had an increase in WBC that was previously not elevated, or a failure to drop the WBC given antibiotics. On the other hand, for the combination of SIRS and elevated white cell count, the CRP, PCT and TTR all give good separation between ICU and non-ICU patients, an improvement over SIRS positive status alone. This reflects the non specificity with a high false positive rate of the SIRS criteria when neither of the two predictors is granulocytosis. We asked whether we can combine the key predictor variable into combinatorial classes that would improve the accuracy of identification. CRP was not of interest with respect to this analysis as the poor specificity could only confound matters, and the test offers no additional information than PCT provides. A more formal classification can then be designed using existing multivariate protocols, but keeping in mind that a mixed model or one using a log-linear model is preferred.

Our study is unique in at least two respects: It is the first to clearly demonstrate a graded response of PCT to severity of infectious challenge. It is also a rare study to use a classification method to study the effect of combinations of variables associated with SIRS and infection on PCT elevation (11-13). We have created a graded classification by using feature extraction and forming an N-length class based on established information principles (Kullback entropy and Akaike Information Criteria). The features used to classify the data were PCT, MAP, TTR, WBC and a SIRS score of at least two. The data was also classified without using PCT in order to establish validity for PCT independently of a classification using the feature being evaluated.The classifications have been extensively examined using one-way ANOVA, Kruskal Wallis analysis by ranks, and latent class analyses. The Kruskal-Wallis analysis by ranks is a powerful tool for comparing the PCT levels within and across feature classes when the variance of PCT values across groups does not have the same distribution and the assumption of normal distribution doesn’t hold. Latent class analysis is a group of methods that can be used to classify data when the data is converted to ordinal classes under the assumption that there is a hidden or “latent” underlying classification. In defining latent classes we assume the criterion of “conditional independence,” so that, each variable is statistically independent of every other variable within each latent class, In our case, latent classes correspond to probabilities for and against the presence of a distinct medical syndrome. In this case we call attention to the classes representing no infection, soft tissue infection, sepsis, and severe sepsis or septic shock. In reality, the variables used to form the classes are not independent, but they are used as ordinal variables and can be ranked in order of importance in forming a classification. There is a paper of some interest with regard to classification and prediction of severe sepsis that finds PCT, lactic acid and aminoterminal pro B-type natriuretic peptide correlating with sepsis severity scores (12) and another using PCT in combination with waveform analysis (13).Classification and prediction has been of particular interest to the corresponding investigator for laboratory procedure validation for more than 10 years (20-22).We provide valuable references to this approach (23-27).

In all respects, we find agreement with a large number of studies, including those recently cited (5-19). PCT has been shown to be useful for discriminating systemic inflammatory response, infection and sepsis (5,6) and identifying a high mortality subgroup with sepsis (15), for identifying sepsis at the onset with either gram negative or gram positive bacteremia (10), for evaluating time to treatment effectiveness (16), and for identifying sepsis in the febrile neutropenic patient (18).

What is it in our findings that makes the results compelling? CRP has been used for many years, although more widely in European countries than in US until the high sensitivity assay association with risk of coronary artery disease generated a new interest in this test. CRP increase is associated with SIRS and its production is driven by the cytokines TNFa and Il6. The liver reprioritises the production of acute phase reactants (CRP, a1 acid glycoprotein [orosomucoid], a1 antitrypsin and transferrin with down-regulation of production of albumin, TTR, transcortin, and other serum transport proteins. However, if this happens in the extreme condition, it also is the case in the more chronic conditions, such as, rheumatoid arthritis and autoimmune diseases, and is a feature of the metabolic syndrome, characterized by type 2 diabetes, obesity, and insulin resistance with or without dyslipidemia. Consequently, CRP is quite high associated with a variety of non-septic conditions. The emergence of PCT as a sepsis biomarker is somewhat serendipidous. The protein is the precursor of the peptide calcitonin, produced in the thyroid. Sepsis appears to upregulate the extrathyroidal production of procalcitonin by vascular endothelium by a mechanism not understood. PCT can be elevated with non-septic shock, such a cardiogenic shock, but it is easy to comprehend that secondary sepsis could occur by loss of gut integrity and bacterial translocation in such a state.

The importance of pneumonia and pyelonephritis as a precursor of sepsis, and the rapid progression of sepsis in the hospitalised ICU patient can’t be taken lightly. The identification of sepsis in the emergency room is problematic because the clinical presentation is variable and not so specific. The SIRS criteria – tachycardia, tachypnea, fever, and leukocytosis – are all common presentations in patients without sepsis. On the one hand, more accurate identification of the patients with sepsis should eliminate many patients who are screened for sepsis and subsequently have negative culture, and should identify patients who require prompt antimicrobial treatment at an early stage.

The progression from SIRS to sepsis to organ failure and septic shock should also be monitored effectively, which depends on the level of PCT reflecting the level of systemic disorder. This would permit the best identification of patients who are improving and those who might require activated protein C intervention. The progression from SIRS to sepsis and beyond is a complex process involving repeated events in the course of the acute illness. This gives even more justification for combining PCT with other measures to manage the septic state.

Conclusion

We have demonstrated a clear relationship between high PCT and both SIRS and the ICU placement of the patient. In addition, we have shown the strength of classifying these patients using PCT in combination with MAP, TTR, WBC and SIRS.

References

1. Martin MS, Mannino DM, et al. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med. 2003; 348:1546-1554.

2. NationalCenter for Health Statistics. National vital statistics reports. 2004; 53:9.

3. Angus DC, Linde-Zwirble WT, et al. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001; 29:1303-1310.

4. Smith BS, Schroeder WS; Tataronis GR.Hospital reimbursement for adult Patients with severe sepsis treated with drotrecogin alfa (activated). Hospital pharmacy 2005; 40:146-153.

5. Assicot M, Gendrel D, Cersin H, Raymond J, et al. High serum procalcitonin concentrations in patients withsepsis and infection. Lancet 1993: 341: 515-18.

6. Delveraux I, Andre M, Columbier M, Albuisson E, et al. Can procalcitonin measurement help in differentiating between bacterial and other kinds of inflammatory processes? Ann Rheum Dis 2003; 62: 337-40.

7. Bone R, Balk R, Cerra F, Dellinger R, Fein W, et. Definitions of sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. Amer Coll of Chest Physicians/Soc of Critical Care Med. Chest 1992; 101(6): 1644-655.

8.Dellinger R, Phillip R, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: Internatl Guidelines for Management of Severe Sepsis and Septic Shock:2008. Crit Care Med 2008; 36(1): 296-377.

9. Bernstein LH and Rucinski R. The relationship between granulocyte maturation and the septic state measurement of granulocyte maturation may improve the early diagnosis of the septic state. Clin Chem Lab Med 2011; DOI 10.1515/CCLM.2011.xxx

10. Ridker PM, Danielson E, Fonseca FAH, Genest J, Gotto AM, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. NEJM 2008; 359: 2195-2207.

11. Jensen JU, Heslet L,; Jensen TH, Espersen K, et al. Procalcitonin increase in early identification of critically ill patients at high risk of mortality. Crit Care Med 2006; 34(10):1-7.

12. Luzzani A, Polati E, Dorizzi R, Rungatscher A, et al. Comparison of procalcitonin and C-reactive protein as markers of sepsis. Critical Care Medicine 2003:31(6):1737-1741.

13. Reith HB, Mittelkotter U, Wagner R, Thiede A. Procalcitonin (PCT) in patients with abdominal sepsis. Intensive Care Med 2000; 26 suppl2: S165-9.

14. Rau B, Steinbach G, Baumgart K, Gansauge F, et al. The clinical value of procalcitonin in the prediction of infected necrosis in acute pancreatitis. Intensive Care Med 2000; 26, suppl2. S159-64.

15. Cheval C, Timsit JF, Garrouste-Orgeas M, Assicot M, et al. Procalcitonin (PCT) is useful in predicting the bacterial origin of an acute circulatory failure in critically ill patients. Intensive Care Med 2000; 26, suppl2 S153-8.

16. Brunkhorst FM, Wegscheider K, Forycki ZF, Brunkhorst R. Procalcitonin for early diagnosis and differentiation of SIRS, sepsis, severe sepsis and septic shock. Intensive Care Med 2000; 26, suppl2 S148-52.

17. Becker KL, Snider R, Nylen ES. Procalcitonin assay in systemic inflammation, infection, and sepsis: clinical utility and limitations. Crit Care Med 2008; 36(3): 941-52.

18. Charles PE, Ladoire S, Aho S, Quenot JP, Doise JM, et al. Serum procalcitonin elevation in critically ill patients at the onset of bacteremia caused by either Gram negative or Gram positive bacteria. BMC Infectious Diseases 2008, 8:38 (http://www.biomedcentral.com/1471-2334/8/38)

19. Wanner GA, Keel M, Steckholzer U, Beier W, Stocker R, Ertel W. Relationship between procalcitonin plasma levels and severity of injury, sepsis, organ failure, and mortality in injured patients. Critical Care Medicine. 2000; 28(4): 950-957.

20. Harbath S, Holeckova K, Froidevaux C, Pittet D, et al. Diagnostic Value of Procalcitonin, Interleukin-6, and Interleukin-8 in Critically Ill Patients Admitted with Suspected Sepsis. Amer J Respir Crit Care Med 2001;164: 396-402.

21. Simon L, Gauvin F, 2 Devendra K. Amre DK,Saint-Louis P, Lacroix J. Serum Procalcitonin and C-Reactive Protein Levels as Markers of Bacterial Infection: A Systematic Review and Meta-analysis. CID 2004: 39:206-217.

22. Selberg O, Hecker H, Martin M, Klos A Bautsch, et al. Discrimination of sepsis and systemic inflammatory response syndrome by determination of circulating plasma concentrations of procalcitonin, protein complement 3a, and interleukin-6. Critical Care Medicine. 2000; 28(8): 2793-2798.

23. Phua J, Koay ES, Lee KH. Lactate, procalcitonin, and amino-terminal pro-B-type natriuretic peptide versus cytokine measurements and clinical severity scores for prognostication in septic shock. Shock 2008; 29(3):328-33.

24. Zakariah AN ; Cozzi SM ; Van Nuffelen M ; Clausi CM ; Pradier O ; Vincent JL. Combination of biphasic transmittance waveform with blood procalcitonin levels for diagnosis of sepsis in acutely ill patients. Crit Care Med. 2008; 36(5): 1507-12

25. Viallon A, Guyomarch S, Marjollet O, Berger C, et al. Can Emergency physicians identify a high mortality subgroup of patients with sepsis: role of procalcitonin? Eur J Emerg Med 2008; 15(1):26-33.

26. Bobre V, Harbarth S, Graf JD, Rohner P, Pugin J. Use of procalcitonin to shorten antibiotic treatment duration in septic patients: a randomized trial. Am J Respir Crit Care Med 2008;177 (5):498-505.

27. Indino P, Lemarchand P, Bady P, de Torrente A, et al. Prospective study on procalcitonin and other systemic infection markers in patients with leukocytosis. Int J Infect Dis 2008;12 (3):319-24.

The role of biomarkers in the diagnosis of sepsis and patient management
Author: L. H. Bernstein, MD
Key words: Systemic Inflammatory Response Syndrome (SIRS), sepsis, septic shock, mean arterial blood pressure (MAP), procalcitonin, combinatorial analysis, effect size
Highlights:
1. The systemic inflammatory response syndrome (SIRS) is an acute response to trauma, burn, or infectious injury characterized by fever, hemodynamic and respiratory changes, and metabolic changes, not all of which are consistently present.
2. The SIRS reaction involves hormonally driven changes in liver glycogen reserves, triggering of lipolysis, lean body proteolysis, and reprioritization of hepatic protein synthesis with up-regulation of synthesis of acute phase proteins and down-regulation of albumin and important circulating transport proteins.
3. Understanding of the processes leads to the identification of biomarkers for identification of sepsis and severe, moderate or early SIRS, which also can hasten treatment and recovery.
4. The SIRS reaction unabated leads to a recurring cycle with hemodynamic collapse from septic shock, indistinguishable from cardiogenic shock, and death.

Summary
By focusing on early and accurate diagnosis of infection in patients suspected of SIRS antibiotic overuse and its associated morbidity and mortality may be avoided, and therapeutic targets may be identified. This discussion investigates the performance of diagnostic algorithms and biomarkers for sepsis in patients presenting with leukocytosis and other findings. Suspected patients are usually identified by WBC above 12,000/L PCT level , SIRS and other criteria, such as serum biomarkers of sepsis. In this writer’s study of 435 patients, procalcitonin alone was a superior marker for sepsis. In patients with sepsis there was a marked increase in PCT (p = 0.0001). PCT was increased in patients requiring ICU admission, heart rate and blood pressure monitoring, and assisted ventilation.(p = 0.0001). Means for SIRS/non-SIRS were: CRP 802/404 mg/L; PCT 20.6/7.5 ng/mL; TTR 87.8/125 mg/L. A comprehensive overview of at least a decade of work is provided.

Introduction
Sepsis is a costly diagnosis in hospitalized patients and carries a high financial risk as a comorbidity and a payment penalty for failure to diagnose in a timely manner (1-4) under the severity of illness CMS reimbursement guidelines as a patient safety hazard, with pneumonia and sepsis among the ten most costly among hospital admissions. A polypeptide identical to a prohormone of calcitonin, procalcitonin, was initially described as a potential marker of bacterial disease by Assicot et al.(5). Procalcitonin is almost undetectable under physiological conditions (pg/ml range), but rises to very high values in response to bacteraemia or fungaemia, and appears to be related to the severity of infection.(6) Sequential measurements in patients with bacteraemia have shown a rapid fall within 48 hours of antibiotic administration. There have been numerous studies of the early recognition of sepsis and related diseases in patients related to admission and intensive care. The consensus
guideline has used a SIRS criteria (7, 8). The SIRS criteria (7,8) include temperature </= 36o C. >= 38o C., heart rate > 90 beats per minute, respiratory rate >20 breaths per minute or PaCO2 < 32 mm of Hg, WBC > 12,000/L or < 4,000/L, or > 10% band forms. For the diagnosis of sepsis (2 or more SIRS criteria and confirmed or suspected infection) the SIRS criteria are insufficient with a very high false positive rate, so that there are medical institutions that require three. The observation of fever, tachypnea, and tachycardia may well not be present early, and the observation of leukocytosis with or without band neutrophilia are unreliable. The use of a plasma lactic acid measurement has been added, but it is basically a reflection of decreased splanchnic circulation to the superior mesenteric artery and liver bed. A better case has been made for absolute neutophilia (9), with an adjustment for high lymphocyte counts in children in the first six months, and for the identification of increased immature myeloid precursors (myelocytes and metamyelocytes). The C-reactive protein, a long established acute phase protein, is not predictive at levels under 520 mg/L because it is elevated in a variety of chronic inflammatory conditions. Moreover, it is infrequently used in adult medical practice for that reason, except for the high sensitivity CRP, which has been shown to be relevant to treatment of coronary heart disease by the Jupiter study (10), but also has raised the question of overuse of the statins with the undesirable side effect of skeletal muscle loss. We can explore the validity of over ten years of studies in Europe and US, showing a debated benefit from using the procalcitonin biomarker (PCT, Brahms)(11-28).
Results
A multivariable study with 435 patients to determine whether procalcitonin alone is a superior marker for sepsis established a difference between patients with and without sepsis , as the increase in PCT with sepsis was significant at p = 0.0001. The PCT was also increased in patients who were admitted to the ICU, requiring assisted ventilation and monitoring of heart rate and blood pressure, significant at p = 0.0001. The highest values occur in septic shock, even though mild elevations are seen with localized infection. A PCT level distinguishes between four subgroups of the population: no infection, local infection, sepsis, and severe sepsis and septic shock. The PCT is very low with no infection and rises to levels above 5 with moderate to severe sepsis. Patients in the ICU with SIRS (vs without) have a mean PCT of 35.2 vs 3.7 ng/ml, a clinically as well as statistically significant increase in PCT (Mann-Whitney, p = 0.0001). On the other hand, patients without SIRS in the ICU also have higher CRP [1] and PCT [2] than those not in ICU (1, p = 0.032; 2, p = 0.004), but the CRP difference just reaches statistical significance while the unexpected PCT increase is a big effect. The means obtained for SIRS/non-SIRS are: CRP [1] 802/404 mg/L; PCT [2] 20.6/7.5 ng/ml; TTR [3] 87.8/125 mg/L. So we see an increase of CRP and PCT with SIRS, as expected, and a decrease in TTR to below 100 mg/L as an obligatory response in relationship to the severity of the inflammatory state. The patients with SIRS and those with sepsis, respectively, had significant elevations of CRP [1] and PCT[2], and decrease of TTR[3] by Mann-Whitney test (SIRS, p = 0.006, CRP [1]; 0.0001, PCT [2]; 0.0001 TTR[3]; sepsis, p = 0.010, CRP [1]; 0.014, PCT [2]; 0.004, TTR [3]).
Finally, we are particularly interested in combinations of variables for predicting infection and the stage of infection using PCT, MAP (mean arterial blood pressure), WBC. The model fit looks good based on the chi-squared statistics.

Degrees of freedom (df) 282 p-value
L-squared (L²) 217.69 1.00
X-squared 235.44 0.98
Cressie-Read 209.15 1.00

aBIC (based on LL) 634
bAIC (based on LL) 495
aBayes Information Criterion, bAkaike’s Information Criterion

Model for Dependent
Class1 Class2 Class3 Class4 Overall
R² 0.7961 0.9136 0.9782 0.6410 0.9319

The chi-squared with a p-value close to 1 indicates that the partitioning of the combinatorial groups is excellent, and the model is not underfit or overfit. A second cluster LCA model using SIRS as covariate also gives a good fit. The p-values are acceptable.
Chi-squared Statistics
Degrees of freedom (df) 258 p-value
L-squared (L²) 248.96 0.65
X-squared 230.62 0.89
Cressie-Read 222.07 0.95
BIC (based on L²) -1238.46
AIC (based on L²) -267.04
Even though CRP has validity for identifying SIRS in our exploratory study, the specificity and its usefulness at a cutoff at 52 mg/dL raised significant concerns with respect to with respect to distinguishing SIRS with and without infection. Keep in mind that large variances in CRP exist between the subgroups, which is problematic because of the CRP elevation in patients with metabolic syndrome and with chronic inflammatory diseases, but not necessarily sepsis. TTR is also decreased, as CRP is elevated, in patients with inflammatory conditions without sepsis.
The data demonstrated a clear relationship between high PCT and both SIRS and the ICU placement of the patient. We also showed the elevation of PCT in concert with severity of infection, as determined by medical record review PWe would expect and find elevations of PCT with pneumonia, deep wounds, and pyelonephritis as well as sepsis, but these patients would be expected to meet the SIRS criteria. Our study was not designed to demonstrate how PCT might detect sepsis in older patients with negative SIRS criteria in the ICU who are on ventilator assistance and who may not develop a febrile response. One has to consider that this is related to PCT elevation being partly independent of the SIRS response.
We then showed the same relationship to biomarker combinations that classify the data in accordance with the severity of infection. The WBC count is the weakest classification variable, but it is in the SIRS criteria and it is of greatest value with a finding of immature neutrophils. However, the band count is now considered part of the mature neutrophil count so that the absolute neutrophil count and the immature granulocytes measured by flow cytometry (myelocytes and metamyelocytes) are superior to the tWBC and bands ( ). The MAP is valuable for identifying the patients at highest risk of circulatory collapse with a drop in the MAP and transfer to ICU (on pressors). The drop in MAP within 72 hours is important for making decisions about Activated protein C (Xygris), which is a critical decision. APC has been removed from the market. We included the TTR, which decreases in patients with SIRS in proportion to the severity of illness. We asked whether we can combine the key predictor variable into combinatorial classes that would improve the accuracy of identification. CRP was not of interest with respect to this analysis as the poor specificity could only confound matters, and the test offers no additional information than PCT provides.
Our study is unique in at least two respects: It is the first to clearly demonstrate a graded response of PCT to severity of infectious challenge. It is also a rare study to use a classification method to study the effect of combinations of variables associated with SIRS and infection on PCT elevation (11-13). We have created a graded classification by using feature extraction and forming an N-length class based on established information principles (Kullback entropy and Akaike Information Criteria). The features used to classify the data were PCT, MAP, TTR, WBC and a SIRS score of at least two. The data was also classified without using PCT in order to establish validity for PCT independently of a classification using the feature being evaluated.The classifications have been extensively examined using one-way ANOVA, Kruskal Wallis analysis by ranks, and latent class analyses. The Kruskal-Wallis analysis by ranks is a powerful tool for comparing the PCT levels within and across feature classes when the variance of PCT values across groups does not have the same distribution and the assumption of normal distribution doesn’t hold. Latent class analysis is a group of methods that can be used to classify data when the data is converted to ordinal classes under the assumption that there is a hidden or “latent” underlying classification. In defining latent classes we assume the criterion of “conditional independence,” so that, each variable is statistically independent of every other variable within each latent class, In our case, latent classes correspond to probabilities for and against the presence of a distinct medical syndrome. In this case we call attention to the classes representing no infection, soft tissue infection, sepsis, and severe sepsis or septic shock. In reality, the variables used to form the classes are not independent, but they are used as ordinal variables and can be ranked in order of importance in forming a classification. There is a paper of some interest with regard to classification and prediction of severe sepsis that finds PCT, lactic acid and aminoterminal pro B-type natriuretic peptide correlating with sepsis severity scores (12) and another using PCT in combination with waveform analysis (13). Classification and prediction has been of particular interest to the corresponding investigator for laboratory procedure validation for more than 10 years (20-22). We provide valuable references to this approach (23-27).
In all respects, we find agreement with a large number of studies, including those recently cited (5-19). PCT has been shown to be useful for discriminating systemic inflammatory response, infection and sepsis (5,6) and identifying a high mortality subgroup with sepsis (15), for identifying sepsis at the onset with either gram negative or gram positive bacteremia (10), for evaluating time to treatment effectiveness (16), and for identifying sepsis in the febrile neutropenic patient (18).
We have demonstrated a clear relationship between high PCT and both SIRS and the ICU placement of the patient. In addition, we have shown the strength of classifying these patients using PCT in combination with MAP, TTR, WBC and SIRS.

References

1. Martin MS, Mannino DM, et al. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med. 2003; 348:1546-1554.
2. National Center for Health Statistics. National vital statistics reports. 2004; 53:9.
3. Angus DC, Linde-Zwirble WT, et al. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001; 29:1303-1310.
4. Smith BS, Schroeder WS; Tataronis GR. Hospital reimbursement for adult Patients with severe sepsis treated with drotrecogin alfa (activated). Hospital pharmacy 2005; 40:146-153.
5. Assicot M, Gendrel D, Cersin H, Raymond J, et al. High serum procalcitonin concentrations in patients withsepsis and infection. Lancet 1993: 341: 515-18.
6. Delveraux I, Andre M, Columbier M, Albuisson E, et al. Can procalcitonin measurement help in differentiating between bacterial and other kinds of inflammatory processes? Ann Rheum Dis 2003; 62: 337-40.
7. Bone R, Balk R, Cerra F, Dellinger R, Fein W, et. Definitions of sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. Amer Coll of Chest Physicians/Soc of Critical Care Med. Chest 1992; 101(6): 1644-655.
8.Dellinger R, Phillip R, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: Internatl Guidelines for Management of Severe Sepsis and Septic Shock:2008. Crit Care Med 2008; 36(1): 296-377.
9. Bernstein LH and Rucinski R. The relationship between granulocyte maturation and the septic state
measurement of granulocyte maturation may improve the early diagnosis of the septic state. Clin Chem Lab Med 2011; DOI 10.1515/CCLM.2011.xxx
10. Ridker PM, Danielson E, Fonseca FAH, Genest J, Gotto AM, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. NEJM 2008; 359: 2195-2207.
11. Jensen JU, Heslet L,; Jensen TH, Espersen K, et al. Procalcitonin increase in early identification of critically ill patients at high risk of mortality. Crit Care Med 2006; 34(10):1-7.
12. Luzzani A, Polati E, Dorizzi R, Rungatscher A, et al. Comparison of procalcitonin and C-reactive protein as markers of sepsis. Critical Care Medicine 2003:31(6):1737-1741.
13. 2008, 8:38 (http://www.biomedcentral.com/1471-2334/8/38)
19. Wanner GA, Keel M, Steckholzer U, Beier W, Stocker R, Ertel W. Relationship between procalcitonin plasma levels and severity of injury, sepsis, organ failure, and mortality in injured patients. Critical Care Medicine. 2000; 28(4): 950-957.
20. Harbath S, Holeckova K, Froidevaux C, Pittet D, et al. Diagnostic Value of Procalcitonin, Interleukin-6, and Interleukin-8 in Critically Ill Patients Admitted with Suspected Sepsis. Amer J Respir Crit Care Med 2001;164: 396-402.
21. Simon L, Gauvin F, 2 Devendra K. Amre DK,Saint-Louis P, Lacroix J. Serum Procalcitonin and C-Reactive Protein Levels as Markers of Bacterial Infection: A Systematic Review and Meta-analysis.
CID 2004: 39:206-217.
22. Selberg O, Hecker H, Martin M, Klos A Bautsch, et al. Discrimination of sepsis and systemic inflammatory response syndrome by determination of circulating plasma concentrations of procalcitonin, protein complement 3a, and interleukin-6. Critical Care Medicine. 2000; 28(8): 2793-2798.
23. Phua J, Koay ES, Lee KH. Lactate, procalcitonin, and amino-terminal pro-B-type natriuretic peptide versus cytokine measurements and clinical severity scores for prognostication in septic shock. Shock 2008; 29(3):328-33.
24. Zakariah AN ; Cozzi SM ; Van Nuffelen M ; Clausi CM ; Pradier O ; Vincent JL. Combination of biphasic transmittance waveform with blood procalcitonin levels for diagnosis of sepsis in acutely ill patients. Crit Care Med. 2008; 36(5): 1507-12
25. Viallon A, Guyomarch S, Marjollet O, Berger C, et al. Can Emergency physicians identify a high mortality subgroup of patients with sepsis: role of procalcitonin? Eur J Emerg Med 2008; 15(1):26-33.
26. Bobre V, Harbarth S, Graf JD, Rohner P, Pugin J. Use of procalcitonin to shorten antibiotic treatment duration in septic patients: a randomized trial. Am J Respir Crit Care Med 2008;177 (5):498-505.
27. Indino P, Lemarchand P, Bady P, de Torrente A, et al. Prospective study on procalcitonin and other systemic infection markers in patients with leukocytosis. Int J Infect Dis 2008;12 (3):319-24.
28. Massaro KS, Costa SF, Leone C, Chamone DA. Procalcitonin (PCT) and C-reactive Protein (CRP) as severe systemic infection markers in febrile neutropenic adults. BMC Infect Dis 2007; 22(7): 137 (http://www.biomedcentral.com/1471-2334-7-137).
29. Vermunt J and Magidson J. Latent Gold 4.5. http://www.statistical.innovations.com

Table 1. Comparison of key sepsis biomarkers by means between ICU and non-ICU, SIRS positive status, and sepsis status.

Marker	Mean		p
SIRS Positive	ICU vs not
CRP (mg/L)	780	495	0.166
PCT (ng/ml)	35.2	3.7	0.0001
SIRS negative	ICU vs not
PCT (ng/ml)			0.0001
Sepsis Diagnosis	ICU vs not
CRP (mg/L)	817	521	0.010
PCT (ng/ml)			0.014
WBC			0.921
% neutrophils			0.452
SIRS with WBC	ICU vs not
CRP (mg/L)	802	404	0.006
PCT (ng/ml)	20.6	7.5	0.0001

Table 2. Comparison of PCT, MAP, TTR and WBC means and variation in SIRS and ICU placement.

variable-by-variable^a	Fisher’s Exact test^b	t-test^c
PCT*SIRS	0.0001	0.0210
PCT*ICU	0.0001	0.0001
MAP*SIRS		0.0130
MAP*ICU	0.0001	0.0001
WBC*SIRS	0.0001	0.0001
WBC*ICU		NS
TTR*SIRS	0.0001	0.0001
TTR*ICU		0.0001

^atwo variables, ^b,cp-value

Archival Table

Table 3. Classes and 4-variable contributions for 4-class LCA cluster model.

Cluster Size

0.3646 0.2738 0.2209 0.1408

Indicators

PCT0425 (PCT: < 0.4, 0.41-2.5, > 2.5)

0 0.6393 0.8894 0.1278 0.0000

1 0.3190 0.1076 0.3752 0.0013

2 0.0355 0.0029 0.2459 0.0285

3 0.0062 0.0001 0.2511 0.9702

MAP758088 (MAP: > 88, 81-87, 75-80, < 80)

0 0.5234 0.6186 0.3709 0.4228

1 0.1861 0.1794 0.1771 0.1828

2 0.1065 0.0838 0.1361 0.1272

3 0.1841 0.1181 0.3160 0.2673

WBC1217 (WBC: < 12, 12-17, > 17)

0 0.3325 0.1772 0.0002 0.3084

1 0.4152 0.3948 0.0216 0.4171

2 0.2523 0.4280 0.9782 0.2745

TTR7105 (TTR: > 10.5, 7.0-10.5, < 7)

0 0.2457 0.9805 0.2159 0.3920

1 0.3352 0.0192 0.3279 0.3391

2 0.4191 0.0003 0.4562 0.2688

Table 1. Comparison of key sepsis biomarkers by means between ICU and non-ICU, SIRS positive status, and sepsis status.

Marker	Mean		p
SIRS Positive	ICU vs not
CRP (mg/L)	780	495	0.166
PCT (ng/ml)	35.2	3.7	0.0001
SIRS negative	ICU vs not
PCT (ng/ml)			0.0001
Sepsis Diagnosis	ICU vs not
CRP (mg/L)	817	521	0.010
PCT (ng/ml)			0.014
WBC			0.921
% neutrophils			0.452
SIRS with WBC	ICU vs not
CRP (mg/L)	802	404	0.006
PCT (ng/ml)	20.6	7.5	0.0001

Table 2. Comparison of PCT, MAP, TTR and WBC means and variation in SIRS and ICU placement.

variable-by-variable^a	Fisher’s Exact test^b	t-test^c
PCT*SIRS	0.0001	0.0210
PCT*ICU	0.0001	0.0001
MAP*SIRS		0.0130
MAP*ICU	0.0001	0.0001
WBC*SIRS	0.0001	0.0001
WBC*ICU		NS
TTR*SIRS	0.0001	0.0001
TTR*ICU		0.0001

^atwo variables, ^b,cp-value

Archival Table

Table 3. Classes and 4-variable contributions for 4-class LCA cluster model.

Cluster Size

0.3646 0.2738 0.2209 0.1408

Indicators

PCT0425 (PCT: < 0.4, 0.41-2.5, > 2.5)

0 0.6393 0.8894 0.1278 0.0000

1 0.3190 0.1076 0.3752 0.0013

2 0.0355 0.0029 0.2459 0.0285

3 0.0062 0.0001 0.2511 0.9702

MAP758088 (MAP: > 88, 81-87, 75-80, < 80)

0 0.5234 0.6186 0.3709 0.4228

1 0.1861 0.1794 0.1771 0.1828

2 0.1065 0.0838 0.1361 0.1272

3 0.1841 0.1181 0.3160 0.2673

WBC1217 (WBC: < 12, 12-17, > 17)

0 0.3325 0.1772 0.0002 0.3084

1 0.4152 0.3948 0.0216 0.4171

2 0.2523 0.4280 0.9782 0.2745

TTR7105 (TTR: > 10.5, 7.0-10.5, < 7)

0 0.2457 0.9805 0.2159 0.3920

1 0.3352 0.0192 0.3279 0.3391

2 0.4191 0.0003 0.4562 0.2688

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SAME SCIENTIFIC IMPACT: Scientific Publishing – Open Journals vs. Subscription-based

Posted in Alzheimer's Disease, Bio Instrumentation in Experimental Life Sciences Research, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, BioSimilars, Bone Disease and Musculoskeletal Disease, CANCER BIOLOGY & Innovations in Cancer Therapy, Cardiovascular Pharmacogenomics, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Computational Biology/Systems and Bioinformatics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Ecosystems & Industrial Concentration in the Medical Device Sector, FDA Regulatory Affairs, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Health Economics and Outcomes Research, HealthCare IT, Infectious Disease & New Antibiotic Targets, Innovations in Neurophysiology & Neuropsychology, International Global Work in Pharmaceutical, Liver & Digestive Diseases Research, Medical and Population Genetics, Medical Devices R&D Investment, Metabolomics, Nutrigenomics, Nutrition, Origins of Cardiovascular Disease, Pain: Etiology, Genetics & Innovations in Treatment, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Analytics, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Investment, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, Proteomics, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Reproductive Biology & Bio Instrumentation, Statistical Methods for Research Evaluation, Systemic Inflammatory Response Related Disorders, tagged BMC Medicine, Bo-Christer Björk, David Solomon, Hanken School of Economics, http://pharmaceuticalintelligence.com, http://www.facebook.com/LeadersInPharmaceuticalBusinessIntelligence, http://www.linkedin.com/groups?gid=4346921&trk=hb_side_g, http://www.linkedin.com/in/avivalevari, https://sites.google.com/site/avivasopusmagnum/aviva-s-home-page, https://twitter.com/#!/pharma_BI, Michigan State University, Open access, Open access journal, Research Methodology, Scientific Web site on July 23, 2012| 1 Comment »

Reporters: Aviva Lev-Ari, PhD, RN & Pnina G. Abir-Am, PhD

Drastic change in academic education by design: FREE ACCESS to knowledge — Program edX – the Harvard+MIT collaboration on Online education!!

FREE ACCESS to Scientific Journals will be the next step. Research to support that by a study carried by Bjork, B. C., and D. Solomon. 2012. Open access versus subscription journals: a comparison of scientific impact. BMC Medicine. 10(1):73+.

“Following step will be to demonstrated that Scientific Websites like http://pharmaceuticalintelligence.com have SAME Scientific impact as Open Journals!!

“We are well positioned to demonstrate that” said Aviva Lev-Ari, PhD, RN, Director & Founder of Leaders in Pharmaceutical Business Intelligence and the 2/2012 launcher of the initiative called http://pharmaceuticalintelligence.com To trace her contributions to Research Methodology, 1976-2005, go to https://sites.google.com/site/avivasopusmagnum/aviva-s-home-page

The merit of Scientific Website is manifold:

Time from Lab/Desk to Publication on the Internet and Search engines is reduced to seconds
comments by other scientists are equally valuable to peer review
collaboration with other scientist around the globe is fostered on WWW
the platform is of collaborative authoring, we have 60 categories of research in one site
interdisciplinary work can be published in one site the over arching domain in our case is Life Sciences, Pharmaceutical and Healthcare

In May 2012 MIT and Harvard are collaborating on distribution of course material of all classes on the Internet – a Program called EdX

http://www.edxonline.org/

In the Press Release“EdX represents a unique opportunity to improve education on our own campuses through online learning, while simultaneously creating a bold new educational path for millions of learners worldwide,” MIT President Susan Hockfield said.

Harvard President Drew Faust said, “edX gives Harvard and MIT an unprecedented opportunity to dramatically extend our collective reach by conducting groundbreaking research into effective education and by extending online access to quality higher education.”

“Harvard and MIT will use these new technologies and the research they will make possible to lead the direction of online learning in a way that benefits our students, our peers, and people across the nation and the globe,” Faust continued.

Princeton, Stanford, Michigan and the University of Pennsylvania announced that they would offer free Web-based courses through a for-profit company called Coursera that was founded by two Stanford computer science professors. One of those professors, Andrew Ng, taught a free online course in machine learning this past fall with an enrollment of more than 100,000 students.

There’s also Udacity, co-founded by a former Stanford professor, andKhan Academy, which boasts 3,100 free educational videos across a variety of subjects.

MIT and Harvard said that they hope to eventually partner with other universities to expand the offerings on the edX platform.

http://www.edxonline.org/release.html

http://money.cnn.com/2012/05/02/technology/harvard-mit-online/index.htm

Results of the BMC Medicine study are reported, below and they are: Open Access, But Same Impact

BioTechniques

http://www.biotechniques.com/news/Open-Access-But-Same-Impact/biotechniques-333012.html#.UA2SsRxueMU

Open Access, But Same Impact

07/19/2012

Jesse Jenkins

By comparing two-year impact factors for journals, researchers found that open access and subscription-based journals have about the same scientific impact.

Open access (OA) journals are approaching the same scientific impact and quality as traditional subscription journals, according to a new study. In a study published in BMC Medicine on July 17 (1), researchers surveyed the impact factors, the average number of citations per paper published in a journal during the two preceding years, of OA and traditional subscription journals.

By comparing two-year impact factors for journals from the four countries that publish the most scientific literature, researchers have found that OA journals have about the same scientific impact as their subscription-based counterparts. Source: BMC Medicine.

At first, the study’s authors—Bo-Christer Björk from the Hanken School of Economics in Helsinki, Finland, and David Solomon from the College of Human Medicine at Michigan State University—found that there was a 30% higher average citation rate for subscription journals. But after controlling for journal discipline, location of publisher, and age of publication, their results showed that OA and subscription journals had nearly identical scientific impact.

“The newer open access published within the last 10 years, particularly those journals funded by article processing fees, had basically the same impact as subscription journals within the same category,” said Solomon. “I think that that is the key finding.”

The initial higher citation rate for subscription journals was the result of a higher percentage of older OA journals from countries that are not major publishing countries. “A lot of them are from South America or other developing countries, and they tend to have lower impact factors,” said Solomon. “When you compare apples to apples and start looking within subgroups, particularly journals launched after 2000 in biomedicine for example, the differences fall away.”

However, the authors identified a sector of low quality, OA publishers that are looking to capitalize on the article processing charge model rather than contribute to the advancement of science. Solomon said that this could partly be to blame for negative perceptions about the integrity of OA publishing as a whole and its impact on the peer review system. But most researchers are aware of these low-quality publishers and prefer to publish in more reputable OA journals.

In the end, Bjork and Solomon are hopeful that the study’s findings may help dispel some of the misconceptions in the debate over OA publishing. “Open access journals still have the reputation of being second class in the minds of some people. So, we think that this is important because this is objective data verifying that at least the open access journals published in the last 10 years by professional publishers are on par with subscription journals.”

References

Bjork, B. C., and D. Solomon. 2012. Open access versus subscription journals: a comparison of scientific impact. BMC Medicine. 10(1):73+.

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