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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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Medicines in Development for Cancer in 2012: An Excellent Response from America’s Biopharmaceutical Research Companies

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, FDA Regulatory Affairs, Genome Biology, Health Economics and Outcomes Research, Personalized and Precision Medicine & Genomic Research, tagged Acute myeloid leukemia, AML, Biopharmaceutical, biopharmaceutical research, Cancer - General, cancer cells, disease, health, new medicines, research, United States on July 31, 2012| 5 Comments »

Reported by: Dr. Venkat S. Karra, Ph.D.

Cancer remains the second leading cause of death by disease. Hundreds of new medicines to treat cancer are now being developed for lessening the burden of cancer to patients, their families and society.

Biopharmaceutical researchers are now working on 981 medicines for cancer. Many are high-tech weapons to fight the disease, while some involve innovative research into using existing medicines in new ways, the report says.

Recent developments in early detection and a steady stream of new and improved treatments suggesting that cancer is a manageable chronic disease (not a deadly one any more). Families and patients alike are with increasing expectations from the industry for more and better treatment options and America’s biopharmaceutical research companies are responding to that.

America’s biopharmaceutical research companies are working on many new cutting-edge approaches to fight cancer. They include:

• A medicine that interferes with the metabolism of cancer cells by depriving them of the energy provided by glucose.
• A medicine for acute myeloid leukemia (AML) that inhibits cancer cells with a mutation found in about a third of AML sufferers.
• A therapy that uses nanotechnology to target the delivery of medicines to cancer cells, potentially overcoming some limitations of existing treatments.

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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Biosimilars: Financials 2012 vs. 2008

Curator: Aviva Lev-Ari, PhD, RN

For IP and Legal aspects of Biosimilars, go to:

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

http://pharmaceuticalintelligence.com/2012/07/30/biosimilars-intellectual-property-creation-and-protection-by-pioneer-and-by-biosimilar-manufacturers/

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/

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

Thus, projection of Sales for Biosmilars as % of top 100 U.S. Pharmaceutical will receive a special meaning and an expected enhanced market share for 2012 year end and beyond 2012.

Biosimilars are occupying the Following ranking in the U.S. Pharmacuetical Sales – 2012: Top 100 Drugs for Q1 2012 by Sales: 10, 11, 12 13, 15, 24, 27, 29, 33, 35, 39, 57, 58, 62, 65, 70, 72, 74, 90, 98, 99. In addition the following biosimilars did not make the Top 100 list:

Biosimilar Drugs by US Sales – not included in the Top 100 Drug List

Recombinate $2.9 1998 — Antihemophilic Factor VIII (Recombinant) by Baxter 5.7 Billion in 2012

Cerezyme $1.5 1994 — Gaucher disease and Fabrazyme for Fabry disease by Genzyme 200 millions in sales

TYSABRI(R) (natalizumab) revenues were $280 million, in-line with the second quarter of 2011 by Elan and Biogen

NovoSeven $1.4 1999 — Anti-fibrinolytics by Novo Nordisk – $1.5Billion

Synagis $1.3 1998 — Generic Name: palivizumab Anti-virals by AstraZeneca $570 millions

Humulin $1.1 1992 Insulin Human by Eli Lilly $ 1.2 Billion

Kogenate FS $1.1 1993 — octocog alfa Anti-fibrinolytics By Bayer $1.4 billion

U.S. Pharmacuetical Sales – 2012: Top 100 Drugs for Q1 2012 by Sales – Small Molecule Drugs (in green) and Biosimilars (in red)

The following is a list of the top 100 pharmaceutical drugs by retail sales in 2012, listed by U.S. sales value and drug name. Last updated: July 2012 (updated quarterly)

http://www.drugs.com/stats/top100/sales

Rank	Drug	Sales ($000)
1	PlavixBristol-Myers Squibb Company	1,620,790	Stats
2	NexiumAstraZeneca Pharmaceuticals	1,395,981	Stats
3	AbilifyOtsuka Pharmaceutical Co.	1,340,200	Stats
4	SingulairMerck & Co., Inc.	1,238,134	Stats
5	SeroquelAstraZeneca Pharmaceuticals	1,161,141	Stats
6	Advair DiskusGlaxoSmithKline	1,139,182	Stats
7	CrestorAstraZeneca Pharmaceuticals	1,117,904	Stats
8	CymbaltaEli Lilly and Company	1,029,262	Stats
9	atorvastatinGeneric Drug	952,407	Stats
10	HumiraAbbott Laboratories	928,124	Stats
11	RemicadeCentocor Ortho Biotech, Inc	899,453	Stats
12	EnbrelAmgen Inc.	890,135	Stats
13	NeulastaAmgen Inc.	849,971	Stats
14	LipitorPfizer Inc	840,715	Stats
15	RituxanGenentech, Inc	756,875	Stats
16	CopaxoneTeva Pharmaceuticals	748,585	Stats
17	AtriplaGilead Sciences, Inc.	694,901	Stats
18	OxyContin	662,876	Stats
19	SpirivaBoehringer Ingelheim Pharmaceuticals, Inc	659,818	Stats
20	AvastinGenentech, Inc	632,183	Stats
21	ActosTakeda Pharmaceuticals North America, Inc	630,970	Stats
22	JanuviaMerck & Co., Inc.	583,603	Stats
23	TruvadaGilead Sciences, Inc.	546,098	Stats
24	LantusSanofi-Aventis	520,584	Stats
25	DiovanNovartis Corporation	509,615	Stats
26	LexaproForest Pharmaceuticals, Inc	491,053	Stats
27	EpogenAmgen Inc.	489,570	Stats
28	LyricaPfizer Inc	458,171	Stats
29	Lantus SolostarSanofi-Aventis	448,388	Stats
30	enoxaparinGeneric Drug	442,263	Stats
31	EloxatinSanofi-Aventis	431,928	Stats
32	CelebrexPfizer Inc	430,993	Stats
33	HerceptinGenentech, Inc	425,687	Stats
34	Diovan HCTNovartis Corporation	415,475	Stats
35	LucentisGenentech, Inc	409,547	Stats
36	SynagisMedImmune, Inc	396,556	Stats
37	NamendaForest Pharmaceuticals, Inc	391,638	Stats
38	GleevecNovartis Corporation	391,072	Stats
39	AvonexBiogen Idec	388,623	Stats
40	VyvanseShire US Inc	387,167	Stats
41	olanzapineGeneric Drug	385,867	Stats
42	IncivekVertex Pharmaceuticals	371,349	Stats
43	One Touch Ultra	366,294	Stats
44	SuboxoneReckitt Benckiser Pharmaceuticals Inc.	338,840	Stats
45	methylphenidateGeneric Drug	337,211	Stats
46	ZetiaMerck & Co., Inc.	328,653	Stats
47	AndroGelAbbott Laboratories	311,850	Stats
48	ProvigilCephalon, Inc.	303,029	Stats
49	LidodermEndo Pharmaceuticals	301,354	Stats
50	TriCorAbbott Laboratories	298,834	Stats
51	SymbicortAstraZeneca Pharmaceuticals	290,669	Stats
52	CombiventBoehringer Ingelheim Pharmaceuticals, Inc	285,487	Stats
53	ProAir HFATeva Pharmaceuticals	284,647	Stats
54	Seroquel XRAstraZeneca Pharmaceuticals	282,416	Stats
55	amphetamine/dextroamphetamineGeneric Drug	275,447	Stats
56	NasonexMerck & Co., Inc.	274,748	Stats
57	NovologNovo Nordisk Inc.	266,305	Stats
58	ProcritJanssen Pharmaceuticals, Inc	264,190	Stats
59	AlimtaEli Lilly and Company	263,024	Stats
60	ViagraPfizer Inc	260,678	Stats
61	GeodonPfizer Inc	260,514	Stats
62	Rebif	258,088	Stats
63	budesonideGeneric Drug	257,243	Stats
64	NiaspanAbbott Laboratories	255,383	Stats
65	HumalogEli Lilly and Company	244,587	Stats
66	Flovent HFAGlaxoSmithKline	241,552	Stats
67	LovazaGlaxoSmithKline	239,845	Stats
68	LevemirNovo Nordisk Inc.	239,576	Stats
69	Adderall XRShire US Inc	239,097	Stats
70	NeupogenAmgen Inc.	238,427	Stats
71	ReyatazBristol-Myers Squibb Company	238,151	Stats
72	AranespAmgen Inc.	231,643	Stats
73	metoprololGeneric Drug	231,395	Stats
74	NovoLog FlexPenNovo Nordisk Inc.	227,228	Stats
75	VytorinMerck & Co., Inc.	218,215	Stats
76	JanumetMerck & Co., Inc.	212,596	Stats
77	IsentressMerck & Co., Inc.	211,526	Stats
78	escitalopramGeneric Drug	210,171	Stats
79	CialisEli Lilly and Company	206,996	Stats
80	AciphexEisai Corporation	203,097	Stats
81	PradaxaBoehringer Ingelheim Pharmaceuticals, Inc	201,065	Stats
82	SolodynMedicis Pharmaceutical Corporation	198,909	Stats
83	fentanylGeneric Drug	197,350	Stats
84	ZyprexaEli Lilly and Company	194,460	Stats
85	VelcadeTakeda Pharmaceuticals North America, Inc	188,583	Stats
86	RestasisAllergan, Inc	188,501	Stats
87	LunestaSunovion Pharmaceuticals Inc.	187,941	Stats
88	acetaminophen/hydrocodoneGeneric Drug	185,374	Stats
89	PrezistaJanssen Pharmaceuticals, Inc	182,859	Stats
90	PegasysGenentech, Inc	181,693	Stats
91	ZyvoxPfizer Inc	179,523	Stats
92	Prevnar 13Wyeth	179,085	Stats
93	LovenoxSanofi-Aventis	178,957	Stats
94	BenicarDaiichi Sankyo	174,619	Stats
95	VESIcareAstellas Pharma US	174,524	Stats
96	Ventolin HFAGlaxoSmithKline	172,707	Stats
97	OrenciaBristol-Myers Squibb Company	172,202	Stats
98	BetaseronBayer Healthcare Pharmaceuticals	172,143	Stats
99	ErbituxBristol-Myers Squibb Company	171,513	Stats
100	DexilantTakeda Pharmaceuticals North America, Inc	171,179	Stats

Source: IMS Health (Midas).

Biosimilars Drugs by US Sales – not included in the Top 100 Drug List

Recombinate $2.9 1998 — Antihemophilic Factor VIII (Recombinant) by Baxter 5.7 Billion in 2012

Cerezyme $1.5 1994 — Gaucher disease and Fabrazyme for Fabry disease by Genzyme 200 millions in sales

TYSABRI(R) (natalizumab) revenues were $280 million, in-line with the second quarter of 2011 by Elan and Biogen

NovoSeven $1.4 1999 — Anti-fibrinolytics by Novo Nordisk – $1.5Billion

Synagis $1.3 1998 — Generic Name: palivizumab Anti-virals by AstraZeneca $570 millions

Humulin $1.1 1992 Insulin Human by Eli Lilly $ 1.2 Billion

Kogenate FS $1.1 1993 — octocog alfa Anti-fibrinolytics By Bayer $1.4 billion

2011 US Sales vs. 2008 US Sales (in Billions) for Top Selling Biologics

Source for 2008 Sales

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

Source for 20011, Q1 2012 Sales

http://www.drugs.com/stats/top100/sales

Drug Name, 2008 Sales, Year approved , Indication

[i.e. Drug Name Enbrel, 2008 Sales $8.0B, Year approved 1998 , Indication RA]

Enbrel $8.0 1998 — RA, psoriatic arthritis, or ankylosing spondylitis indication

Q1 2012	12 (1)	$890,135	1.92%	823	-4.63%
Q4 2011	11 (1)	$873,343	1.67%	863	1.77%
Q3 2011	12 (1)	$858,997	1.27%	848	-2.97%
Q2 2011	13 (2)	$848,230	3.77%	874	3.19%
Q1 2011	11	$817,401		847

http://www.drugs.com/stats/enbrel

Remicade $7.9 1998 — RA & Chron’s Disease

Q1 2012	11 (2)	$899,453	10.04%	1,556	10.04%
Q4 2011	13 (3)	$817,365	-7.02%	1,414	-9.82%
Q3 2011	10	$879,054	1.52%	1,568	1.03%
Q2 2011	10 (2)	$865,903	7.61%	1,552	7.11%
Q1 2011	12	$804,699		1,449

http://www.drugs.com/stats/remicade

Humira $7.3 2002 — treat rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, and plaque psoriasis

Q1 2012	10	$928,124	2.50%	546	-2.85%
Q4 2011	10 (1)	$905,527	3.18%	562	2.55%
Q3 2011	11 (3)	$877,641	3.95%	548	3.01%
Q2 2011	14	$844,296	6.32%	532	2.31%
Q1 2011	14	$794,076		520

http://www.drugs.com/stats/humira

Rituxan $7.3 1997 — cancer medicines to treat non-Hodgkin’s lymphoma or chronic lymphocytic leukemia.

Q1 2012	15 (1)	$756,875	-1.91%	547	-0.91%
Q4 2011	14 (2)	$771,622	6.96%	552	4.74%
Q3 2011	16	$721,408	-1.77%	527	-1.86%
Q2 2011	16 (4)	$734,378	7.26%	537	5.09%
Q1 2011	20	$684,666

http://www.drugs.com/stats/rituxan

Second Quarter 2012 Highlights: RITUXAN(R) (rituximab) revenues from our unconsolidated joint business arrangement were $285 million for the quarter, an increase of 31% year-over-year. As previously disclosed, during the second quarter of 2011 our share of RITUXAN revenues from unconsolidated joint business was reduced by approximately $50 million to reflect our share of damages and interest that might be awarded in relation to an intermediate decision in Genentech, Inc.’s ongoing arbitration with Hoechst GmbH

http://www.marketwatch.com/story/correcting-and-replacing-biogen-idec-increases-revenue-18-to-14-billion-in-the-second-quarter-2012-07-24

Herceptin $5.7 1998 — treat metastatic breast cancer that has progressed after treatment with other chemotherapy

Q1 2012	33	$425,687	-0.06%	155
Q4 2011	33 (2)	$425,931	7.61%	155	4.73%
Q3 2011	31 (1)	$395,804	-0.64%	148	-0.67%
Q2 2011	32 (4)	$398,348	3.62%	149	1.36%
Q1 2011	36	$384,428		147

http://www.drugs.com/stats/herceptin

Lantus $5.1 2000 — long-acting form of the hormone insulin.

Q1 2012	29 (5)	$448,388	9.81%	3,737	7.32%
Q4 2011	34	$408,336	8.54%	3,482	7.07%
Q3 2011	34 (2)	$376,208	4.53%	3,252	6.00%
Q2 2011	36 (5)	$359,907	7.80%	3,068	8.30%
Q1 2011	41	$333,878		2,833

http://www.drugs.com/stats/lantus-solostar

Epogen/Procrit $5.1 1989 — Anemia, low RBC

Worldwide, sales of the two drugs – sold under the brand names Epogen, Procrit and Aranesp – exceeded $9 billion in 2005 for Amgen and Johnson & Johnson, their makers. Johnson & Johnson, which sells epoetin under the brand names Procrit in the United States and Eprex everywhere else, reported sales of $2.4 billion in the first nine months of 2006, down slightly from 2005.

Amgen Recalls Anemia Medications for Glass Fragments

09/24/2010 – Drug-makers Amgen (AMGN) and Johnson & Johnson (JNJ) are voluntarily recalling two brandsof an injectable anemia medication because vials containing the drug may have tiny glass flakes. The drug, Epoetin alfa, is marketed under the brand names Epogen and Procrit.Known as lamellae, the glass fragments are created by the interaction of the drug with glass vials during storage, Amgen said in a statement announcing the recall. The recall is being conducted in cooperation with the Food and Drug Administration, Amgen said.

http://www.dailyfinance.com/2010/09/24/amgen-recalls-epogen-procrit-glass-anemia-drugs/

http://healthfully.org/dnd/id9.html

Latest study shows anemia drugs Epogen, Aranesp and Procrit cause strokes, says FDA

Posted on January 7, 2010

Anemia drugs sold by Amgen and Johnson & Johnson have been reported to cause strokes when prescribed in high doses, according to an article from the FDA, recently published in the The New England Journal of Medicine. The law firm of Aylstock, Witkin, Kreis & Overholtz is investigating the FDA’s recent announcement.

The FDA commentary said the latest study and previous studies “raise major concerns” about the use of these drugs to treat anemia caused by kidney disease. The drugs are also used to treat anemia caused by chemotherapy. Studies over the past several years have revealed a link between the drugs and heart attacks, strokes, and other problems.

Amgen’s anemia drugs include Epogen and Aranesp. Johnson & Johnson sells anemia drug Procrit, which is produced by Amgen. The drugs are designed to raise red blood cell levels, to promote delivery of oxygen to body tissues.

http://www.awkolaw.com/news/heart-attacks/anemia-drugs-epogen-aranesp-procrit-cause-strokes-says-fda/

Epogen / Procrit / Aranesp: The July 2012 News Report Which Tells Story Of Big Pharma Profits Over Patient Safety And Drug Efficacy

Once The FDA Started Paying Attention The Writing On The Wall Became Apparent, Albeit Too Late For Some

(Posted by Tom Lamb at DrugInjuryWatch.com)

This lengthy and well-presented news report, “Anemia drugs made billions, but at what cost?”, written by Peter Whoriskey and published July 19, 2012 by The Washington Post (free registration required), is a must-read for anyone with a concern or interest in how larger pharmaceutical companies might put corporate profits ahead of patient safety and drug efficacy.

Here is an excerpt from this Washington Post article which will give you a sense of what went on that, in hindsight, is so disturbing:

For years, a trio of anemia drugs known as Epogen, Procrit and Aranesp ranked among the best-selling prescription drugs in the United States, generating more than $8 billion a year for two companies, Amgen and Johnson & Johnson. Even compared with other pharmaceutical successes, they were superstars. For several years, Epogen ranked as the single costliest medicine under Medicare: U.S. taxpayers put up as much as $3 billion a year for the drugs.

The trouble, as a growing body of research has shown, is that for about two decades, the benefits of the drug — including “life satisfaction and happiness” according to the FDA-approved label — were wildly overstated, and potentially lethal side effects, such as cancer and strokes, were overlooked.

Last year, Medicare researchers issued an 84-page study declaring that among most kidney patients, the original and largest market for the drugs, there was no solid evidence that they made people feel better, improved their survival or had any “clinical benefit” besides elevating a statistic for red blood cell count.

As for some of the key events which led up to this revelation of sorts, we start with a June 24, 2011 FDA press release, “FDA modifies dosing recommendations for Erythropoiesis-Stimulating Agents — Cites increased risk of cardiovascular events when used to treat chronic kidney disease”, which included the following:

The U.S. Food and Drug Administration today recommended more conservative dosing guidelines for Erythropoiesis-Stimulating Agents (ESAs) when used to treat anemia in patients with chronic kidney disease (CKD) because of the increased risks of cardiovascular events such as stroke, thrombosis, and death….

http://www.drug-injury.com/druginjurycom/2012/07/epogen-procrit-aranesp-stroke-thrombosis-death-side-effects-safety-risks-benefits-efficacy-fda.html

Procrit — (epoetin alfa) is a man-made form of a protein that helps your body produce red blood cells

Q1 2012	58 (3)	$264,190	-2.13%	295	-4.22%
Q4 2011	55 (2)	$269,937	3.58%	308	3.01%
Q3 2011	53 (12)	$260,610	-21.61%	299	-21.32%
Q2 2011	41 (7)	$332,466	7.04%	380	5.56%
Q1 2011	48	$310,606		360

http://www.drugs.com/stats/procrit

Epogen — (epoetin alfa) is a man-made form of a protein that helps your body produce red blood cells

Q1 2012	27 (7)	$489,570	-24.54%	555	-17.04%
Q4 2011	20 (2)	$648,794	4.67%	669	3.40%
Q3 2011	22 (2)	$619,828	-13.96%	647	-18.41%
Q2 2011	20 (1)	$720,376	3.32%	793	4.48%
Q1 2011	19	$697,224		759

http://www.drugs.com/stats/epogen

Neulasta $4.2 2002 — used to prevent neutropenia, a lack of certain white blood cells caused by receiving chemotherapy. stimulates the bone marrow and promotes the growth of white blood cells called neutrophils

Q1 2012	13 (1)	$849,971	3.33%	331	1.53%
Q4 2011	12 (2)	$822,578	4.59%	326	3.49%
Q3 2011	14 (1)	$786,464	-3.86%	315	-5.69%
Q2 2011	15	$818,068	4.04%	334	3.41%
Q1 2011	15	$786,288		323

http://www.drugs.com/stats/neulasta

Novolog $3.7 2000 — Insulin aspart is a fast-acting form of insulin. NovoLog is used to treat type 1 (insulin-dependent) diabetes in adults and children who are at least 2 years old. It is usually given together with a long-acting insulin.

Q1 2012	57 (6)	$266,305	5.67%	2,980	3.72%
Q4 2011	63 (3)	$252,015	0.97%	2,873	-0.48%
Q3 2011	60 (1)	$249,591	-0.96%	2,887	-2.66%
Q2 2011	61 (5)	$252,010	3.16%	2,966	-0.70%
Q1 2011	66	$244,297		2,987

http://www.drugs.com/stats/novolog

Erbitux $3.6 2004 — used to treat cancers of the colon and rectum. It is also used to treat head and neck cancer.

Q1 2012	99 (2)	$171,513	2.30%	266	3.91%
Q4 2011	97 (7)	$167,657	-0.15%	256	0.79%
Q3 2011	90 (3)	$167,909	-2.48%	254	-1.93%
Q2 2011	93 (2)	$172,185	-0.89%	259	-0.38%
Q1 2011	95	$173,735		260

http://www.drugs.com/stats/erbitux

Aranesp $3.2 2001 — Anemia, low RBC, (darbepoetin alfa) is a man-made form of a protein that helps your body produce red blood cells.

Q1 2012	72 (6)	$231,643	-5.86%	293	-7.86%
Q4 2011	66 (15)	$246,056	-6.07%	318	-3.64%
Q3 2011	51 (3)	$261,967	-10.25%	330	-11.29%
Q2 2011	48 (3)	$291,873	-1.03%	372	-1.33%
Q1 2011	51	$294,912		377

http://www.drugs.com/stats/aranesp

The article reports on the decline of worldwide sales of Aranesp drug from Thousand Oaks, California-based Amgen Inc. as of the second quarter of 2007. According to Amgen, the 10% decrease of Aranesp worldwide sales was due to the reimbursement issues related to the anemia drug and the drop of U.S. demand for drug, in which the U.S. Aranesp reported sales in the second quarter of 2007 was only $578 million from $713 million in 2006.

http://connection.ebscohost.com/c/articles/26375335/amgen-posts-lower-aranesp-sales

1/24/2011, Amgen boosts prices to offset Aranesp sales

Amgen is hiking prices to make up for the shrinking sales volume of its anemia drug Aranesp. Bloomberg reports that Amgen raised the price tag on Aranesp itself by 4.4 percent, but also marked up the white-blood-cell-boosting meds Neulasta and Neupogen by 2.9 percent.

http://www.fiercepharma.com/story/amgen-boosts-prices-offset-aranesp-sales/2011-01-24

Recombinate $2.9 1998 — Antihemophilic Factor VIII (Recombinant)

BioScience core franchises include: Hemophilia, Biotherapeutics, BioSurgery and Vaccines. BioScience products represent approximately 45 percent of Baxter’s annual sales, totaling $5.7 billion in 2010.

2007 Outlook – Sales within Baxter’s BioScience business totaled $1.2 billion, an increase of 18 percent from the same period last year. This growth was driven by record sales of ADVATE, Antihemophilic Factor (Recombinant), Plasma/Albumin Free Method (rAHF-PFM) for the treatment of hemophilia A, antibody therapy products, including GAMMAGARD LIQUID(TM) [Immune Globulin Intravenous (Human)] (IVIG) 10% Solution for the treatment of primary immunodeficiencies, specialty plasma therapeutics and biosurgery products. Medication Delivery sales increased 7 percent to $1.0 billion, with increased sales of infusion systems, intraveneous solutions and parenteral nutrition products, along with accelerated growth in the company’s drug delivery business. Renal sales increased 6 percent to $537 million reflecting accelerating gains in peritoneal dialysis patients globally.

http://www.drugs.com/news/baxter-s-fourth-quarter-financial-results-exceed-expectations-5128.html

Lucentis $2.7 2006 intraocular injection. (ranibizumab injection) is a recombinant humanized IgG1 kappa isotype monoclonal antibody fragment designed for intraocular use. Ranibizumab binds to and inhibits the biologic activity of human vascular endothelial growth factor A (VEGF-A).

Date Range	Sales Rank	Sales ($000)		Units (000)
Q1 2012	35 (5)	$409,547	-6.89%	224	-5.88%
Q4 2011	30 (2)	$439,867	2.44%	238	2.59%
Q3 2011	28 (2)	$429,393	1.13%	232	0.87%
Q2 2011	30 (3)	$424,611	0.95%	230	1.32%
Q1 2011	33	$420,635		227

http://www.drugs.com/stats/lucentis

http://www.gene.com/gene/about/ir/historical/product-sales/lucentis.html

Lucentis brought in $1.7 billion for Roche last year, according to data compiled by Bloomberg.Alimera Sciences Inc. (ALIM), based in Alpharetta, Georgia, and Psivida Corp. (PSDV) also are developing a diabetic macular edema treatment known as Iluvien. The FDA has twice rejected Iluvien, most recently in November.

The FDA pooled results from two Roche clinical trials and found 39 percent of patients who used the 0.3 milligram dose were able to read three additional lines of letters on an eye chart after two years compared to 41 percent who had the same effect on the 0.5 milligram dose, according to an FDA staff report released July 24.

Genentech recommended approval of the 0.3 milligram dose in its application to the FDA since there isn’t evidence of additional benefit of the higher dose, Terence Hurley, a spokesman for the company, said in an e-mail.

Patients who received the monthly injection also were significantly more likely than those who received fake doses of the drug to achieve 20/40 vision, enough eyesight to drive.

http://www.bloomberg.com/news/2012-07-26/roche-s-lucentis-backed-by-fda-panel-for-diabetic-blindness-1-.html

Avonex $2.6 1996 — Multiple Sclerosis, a form of protein called beta interferon that occurs naturally in the body. Interferons help the body fight viral infections. Avonex is used to treat patients with relapsing forms of multiple sclerosis to slow the accumulation of physical disability. This medication will not cure MS, it will only decrease the frequency of relapse symptoms.

Q1 2012	39 (1)	$388,623	2.22%	130	-3.70%
Q4 2011	38 (5)	$380,189	0.19%	135	-2.17%
Q3 2011	33	$379,457	-0.05%	138	-1.43%
Q2 2011	33 (4)	$379,639	2.45%	140	-1.41%
Q1 2011	37	$370,570		142

http://www.drugs.com/stats/avonex

Second-quarter net income surged 34 percent to $386.8 million, or $1.61 a share, from $288 million, or $1.18, a year earlier, the Weston, Massachusetts-based company said today in a statement. Earnings excluding some items of $1.82 topped by 26 cents the average of 21 analysts’ estimates (BIIB) compiled by Bloomberg. Revenue beat estimates by about $90 million.

Biogen said profit this year is expected to be more than $6.20 a share, 5 cents higher than its May 1 forecast (BIIB). The company has been increasing sales of Avonex, Rituxan and Tysabri, another MS therapy, while developing new medicines to introduce to the market.

http://www.businessweek.com/news/2012-07-24/biogen-second-quarter-profit-rises-as-avonex-sales-increase

AVONEX(R) (interferon beta-1a) revenues increased 16% year-over-year to $762 million.

http://www.marketwatch.com/story/correcting-and-replacing-biogen-idec-increases-revenue-18-to-14-billion-in-the-second-quarter-2012-07-24

Novolin $2.5 1991 — Novolin R (insulin regular) is a short-acting form of human insulin, Diabetes, Type 1 Type 2

Date Range	Sales Rank	Sales ($000)		Units (000)
Q1 2012	74 (2)	$227,228	8.96%	2,489	13.81%
Q4 2011	76 (4)	$208,552	10.19%	2,187	6.73%
Q3 2011	80 (6)	$189,267	4.15%	2,049	4.92%
Q2 2011	86 (7)	$181,733	3.71%	1,953	29.60%
Q1 2011	93	$175,235		1,507

http://www.drugs.com/stats/novolog-flexpen

Novo Nordisk launches iPhone app Posted 17th September 2010, 15:11:54

An iPhone app has been launched by Novo Nordisk in the US which lets healthcare staff check dosage guidelines for diabetes patients.

Novo Dose provides product-specific data for the company’s insulin analog agents Levemir (insulin detemir), NovoLog (insulin aspart) and NovoLog Mix (insulin aspart protamine/insulin aspart injectable).

Combined sales of the three medications increased by 24% last year, feeding a double-digit growth in Novo Nordisk sales and profits.

Novo Dose, the second diabetes app created by the industry, tells professionals when and how to dose the drugs, how to titrate and provides information on the blood glucose goals of patients.

Commenting on the new technology, Anup Kumar Sabharwal, an endocrinologist at the University of Miami Clinics’ Diabetes Research Institute, said: “This is where modern medicine is headed.”

Humalog $2.2 1996 Humalog is used to treat type 1 (insulin-dependent) diabetes in adults. Insulin lispro is a fast-acting form of insulin. It is usually given together with another long-acting insulin. It works by lowering levels of glucose in the blood. Humalog is also used together with oral (taken by mouth) medications to treat type 2 (non insulin-dependent) diabetes in adults.

Q1 2012	65	$244,587	-2.70%	2,570	-3.85%
Q4 2011	65 (2)	$251,367	3.78%	2,673	2.81%
Q3 2011	63 (4)	$242,208	-0.75%	2,600	-1.78%
Q2 2011	67 (5)	$244,050	4.83%	2,647	1.15%
Q1 2011	72	$232,809		2,617

http://www.drugs.com/stats/humalog

Pegasys $2.0 2002 — (peginterferon alfa-2a) is made from human proteins that help the body fight viral infections. Pegasys is used to treat chronic hepatitis B or C. It is often used together with another medication called ribavirin (Copegus, Rebetol, RibaPak, Ribasphere, RibaTab).

Q1 2012	90 (1)	$181,693	3.92%	87	3.57%
Q4 2011	91 ()	$174,833		84

http://www.drugs.com/stats/pegasys

Rebif $1.7 2002 — (interferon beta-1a) is a protein identical to one found in the body. Interferon beta-1a is made from human proteins. Interferons help the body fight viral infections. Rebif is used to treat relapsing multiple sclerosis (MS). This medication will not cure MS, it will only decrease the frequency of relapse symptoms.

Q1 2012	62 (1)	$258,088	-0.21%	540	-9.09%
Q4 2011	61 (7)	$258,643	0.43%	594	-0.34%
Q3 2011	54 (5)	$257,535	1.48%	596	-1.49%
Q2 2011	59 (2)	$253,780	0.25%	605	-0.66%
Q1 2011	61	$253,143		609

http://www.drugs.com/stats/rebif

Cerezyme $1.5 1994 — Gaucher disease and Fabrazyme for Fabry disease.

Last year Genzyme was forced to temporarily close its manufacturing plant in Boston due to a viral contamination. The interruption lead to shortages of two key drugs: Cerezyme for Gaucher disease and Fabrazyme for Fabry disease.

That crisis sent the company’s stock price plummeting from nearly $84 in 2008 to a low earlier this year of $45.39. Sanofi’s offer to acquire the company for $18.5 billion, or $69 a share — along with a 14 percent rise in the NYSE Arca Biotech Index since late July — have helped the shares rebound.

But Genzyme is now on a mission to prove to shareholders that it is worth more than Sanofi is offering, and executives told investors on a conference call that the third quarter marks the beginning of its financial turnaround.

Third-quarter sales of Cerezyme, the company’s top drug, rose to $179.8 million from $93.6 million a year earlier, beating analysts’ average forecast of $175 million.

“In the third quarter we saw our financial recovery start to take effect, and we expect that this will accelerate during the fourth quarter as Cerezyme patients are able to return to normal dosing levels and we begin to increase shipments of Fabrazyme,” Genzyme CEO Henri Termeer said in a statement.

http://www.reuters.com/article/2010/10/20/us-genzyme-idUSTRE69J2S520101020

Cerezyme is the principal drug for Gaucher patients. In the first quarter of 2012 Genzyme (now part of Sanofi (SNY))reported Cerezyme sales of 149 million euros (approx. $194 million), up 5.8% from the same quarter of the previous year. The other supplier Shire (SHPGY) reported $72 million in Vpriv sales, up 22%. There is now a third supplier, Pfizer (PFE), teamed up with the Israeli company Protalix Biotherapeutics (PLX), whose product was approved by the FDA in May 2012. Elelyso (taliglucerase alfa) is now available in the US.

http://seekingalpha.com/article/694801-gaucher-disease-the-fight-for-market-share

Product	Cerezyme
	2009	2010	2011
Total	793	720	885
Ann. Growth Total		-9%	23%

http://www.evaluatepharma.com/Universal/View.aspx?type=Entity&entityType=Product&lType=modData&id=15461&componentID=1002

Tysabri $1.4 2004 — Multiple Sclerosis by Elan and Biogen

Global in-market sales of TYSABRI in the second quarter of 2012 were $395 million, an increase of 2% over the second quarter of 2011. The total was comprised of $211 million in U.S. sales and $184 million in sales outside the U.S.

http://www.marketwatch.com/story/correcting-and-replacing-biogen-idec-increases-revenue-18-to-14-billion-in-the-second-quarter-2012-07-24

TYSABRI(R) (natalizumab) revenues were $280 million, in-line with the second quarter of 2011.

http://www.marketwatch.com/story/correcting-and-replacing-biogen-idec-increases-revenue-18-to-14-billion-in-the-second-quarter-2012-07-24

ITALIAN DISPUTE

Elan derives its revenue almost exclusively from Tysabri and it reported total sales for the three months to June 30 of $288 million, up 6 percent on a year ago once sales from its since-divested drug delivery business are omitted.

That compared to the $299 million forecast by four analysts surveyed by Reuters and was driven by in-market sales of Tysabri that rose 2 percent year-on-year to $395 million, also shy of the $419 million expected by analysts.

Biogen, which detailed the sales numbers when it reported second quarter results on Tuesday, attributed the softer-than-expected Tysabri sales to a dispute with the Italian government over pricing.

The number of patients on Tysabri rose 4 percent to 69,100, maintaining Elan and Biogen’s 10 to 12 percent share of the MS drug market in the face of competition from Swiss drugmaker Novartis AG’s Gilenya treatment, the first multiple sclerosis pill to come on the market.

The average addition of 185 new patients per week was the highest quarterly run-rate since the fourth quarter of 2009.

http://in.reuters.com/article/2012/07/25/elan-idINL6E8IP1VV20120725

NovoSeven $1.4 1999 — Anti-fibrinolytics by Novo Nordisk —

Generic Name:

eptacog alfa

Product	NovoSeven
	2009	2010	2011
Total	1,324	1,431	1,559
Ann. Growth Total		8%	9%

http://www.evaluatepharma.com/Universal/View.aspx?type=Entity&entityType=Product&id=13483&lType=modData&componentID=1002

Synagis $1.3 1998 — Generic Name: palivizumab Anti-virals by AstraZeneca

Product	Synagis
	2009	2010	2011
Total	1,042	906	570
Ann. Growth Total		-13%	-37%

http://www.evaluatepharma.com/Universal/View.aspx?type=Entity&entityType=Product&lType=modData&id=91&componentID=1002

Neupogen $1.3 1991 — (filgrastim) is a man-made form of a protein that stimulates the growth of whiteblood cells in your body. White blood cells help your body fight against infection. Neupogen is used to treat neutropenia, a lack of certain white blood cells caused by cancer,bone marrow transplant, receiving chemotherapy, or by other conditions.

Q1 2012	70	$238,427	0.06%	170	-2.86%
Q4 2011	70 (5)	$238,289	0.16%	175	10.76%
Q3 2011	65 (5)	$237,915	0.69%	158	0.64%
Q2 2011	70 (4)	$236,294	2.51%	157	0.64%
Q1 2011	74	$230,515		156

http://www.drugs.com/stats/neupogen

Betaseron $1.2 1993 — (interferon) is made from human proteins. Interferons help the body fight viral infections. Betaseron is used to treat relapsing multiple sclerosis (MS). Betaseron will not cure MS, it will only decrease the frequency of relapse symptoms.

Q1 2012	98 (1)	$172,143	2.93%	67	-10.67%
Q4 2011	99 (12)	$167,236	-3.76%	75	-5.06%
Q3 2011	87 (2)	$173,769	-2.89%	79	-2.47%
Q2 2011	89 (4)	$178,938	-2.17%	81	-7.95%
Q1 2011	85	$182,908		88

http://www.drugs.com/stats/betaseron

Humulin $1.1 1992 Insulin Human by Eli Lilly

Product	Humulin R
	2009	2010	2011
Total	1,022	1,089	1,249
Ann. Growth Total		7%	15%

http://www.evaluatepharma.com/Universal/View.aspx?type=Entity&entityType=Product&lType=modData&id=12399&componentID=1002

Kogenate FS $1.1 1993 — octocog alfa Anti-fibrinolytics By Bayer

Product	Kogenate
	2009	2010	2011
Total	1,238	1,332	1,496
Ann. Growth Total		8%	12%

http://www.evaluatepharma.com/Universal/View.aspx?type=Entity&entityType=Product&lType=modData&id=11681&componentID=1002

Conclusion

REFERENCES

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

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Alcohol Could Intensify Effects of Some Drugs in the Body

Posted in Biological Networks, Gene Regulation and Evolution, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease on July 29, 2012| 1 Comment »

Reporter: Prabodh Kandala, PhD

Scientists are reporting another reason — besides possible liver damage, stomach bleeding and other side effects — to avoid drinking alcohol while taking certain medicines. Their report in ACS’ journal Molecular Pharmaceutics describes laboratory experiments in which alcohol made several medications up to three times more available to the body, effectively tripling the original dose.

Christel Bergström and colleagues explain that beverage alcohol, or ethanol, can cause an increase in the amount of non-prescription and prescription drugs that are “available” to the body after taking a specific dose. Alcohol can change how enzymes and other substances in the body interact with many of the 5,000 such medications on the market. Some of these medications don’t dissolve well in the gastrointestinal tract — especially in the stomach and intestines. The researchers sought to test whether ethanol made these drugs dissolve more easily. If so, this would make the drugs more available in the body, possibly intensifying their effects when combined with alcohol.

To find out, the scientists used a simulated environment of the small intestine to test how rapidly medications dissolved when alcohol was and was not present. Almost 60 percent of the 22 medications in their tests dissolved much faster in the presence of alcohol. In addition, they found that certain types of substances, such as those that were acidic, were more affected. Some common acidic drugs include warfarin, the anticoagulant; Tamoxifen, used to treat certain forms of cancer; and naproxen, which relieves pain and inflammation.

Abstract:

Ethanol intake can lead to an unexpected and possibly problematic increase in the bioavailability of druglike compounds. In this work we investigated the effect of ethanol on the apparent solubility and dissolution rate of poorly soluble compounds in simulated intestinal fluid representing a preprandial state. A series of 22 structurally diverse, poorly soluble compounds were measured for apparent solubility and intrinsic dissolution rate (37 °C) in phosphate buffer pH 6.5 (PhB_6.5) and fasted state simulated intestinal fluid (FaSSIF, pH 6.5) with and without ethanol at 5% v/v or 20% v/v. The obtained data were used to understand for which molecules ethanol results in an increased apparent solubility and, therefore, may increase the amount of drug absorbed. In FaSSIF_20%ethanol 59% of the compounds displayed >3-fold higher apparent solubility than in pure FaSSIF, whereas the effects of 5% ethanol on solubility, in most cases, were negligible. Acidic and neutral compounds were more solubilized by the addition of ethanol than by lecithin/taurocholate aggregates, whereas bases showed a more substance-specific response to the additives in the buffer. The stronger solubilizing capacity of ethanol as compared to the mixed lipid aggregates in FaSSIF was further identified through Spearman rank analyses, which showed a stronger relationship between FaSSIF_20%ethanol and PhB_{6.5,20%ethanol} (r_S of 0.97) than FaSSIF_20%ethanol and FaSSIF (r_S of 0.86). No relationships were found between solubility changes in media containing ethanol and single physicochemical properties, but multivariate data analysis showed that inclusion of ethanol significantly reduced the negative effect of compound lipophilicity on solubility. For this data set the higher concentration of ethanol gave a dose number (Do) <1 for 30% of the compounds that showed incomplete dissolution in FaSSIF. Significant differences were shown in the melting point, lipophilicity, and dose profiles between the compounds having a Do < 1 and Do > 1, with the latter having higher absolute values in all three parameters. In conclusion, this study showed that significant effects of ethanol on apparent solubility in the preprandial state can be expected for lipophilic compounds. The results herein indicate that acidic and neutral compounds are more sensitive to the addition of ethanol than to the mixed lipid aggregates present in the fasted intestine.

Ref:

http://www.sciencedaily.com/releases/2012/07/120726153953.htm

http://pubs.acs.org/doi/abs/10.1021/mp2006467

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Bone Marrow Transplant Eliminates Signs of HIV Infection

Posted in Biological Networks, Gene Regulation and Evolution, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits on July 29, 2012| Leave a Comment »

Reporter: Prabodh Kandala, PhD

Two men with longstanding HIV infections no longer have detectable HIV in their blood cells following bone marrow transplants. The virus was easily detected in blood lymphocytes of both men prior to their transplants but became undetectable by eight months post-transplant. The men, who were treated at Brigham and Women’s Hospital (BWH), have remained on anti-retroviral therapy.

Their cases will be presented on July 26, 2012 at the International AIDS Conference by Timothy Henrich, MD and Daniel Kuritzkes, MD, physician-researchers in the Division of Infectious Diseases at BWH.

“This gives us some important information,” said Dr. Kuritzkes. “It suggests that under the cover of anti-retroviral therapy, the cells that repopulated the patient’s immune system appear to be protected from becoming re-infected with HIV.”

One patient’s bone marrow transplant was two years ago, the other was four years ago. Both were performed at the Dana-Farber/Brigham and Women’s Cancer Center. Over time, as the patients’ cells were replaced by donor cells, traces of HIV were lost. Currently, both patients have no detectable HIV DNA or RNA in their blood. The level of HIV antibody, a measure of exposure to HIV, also declined in both men.

“We expected HIV to vanish from the patients’ plasma, but it is surprising that we can’t find any traces of HIV in their cells,” said Dr. Henrich. “The next step is to determine if there are any traces of HIV in their tissue.”

The research team is currently designing studies that would enable them to look for HIV in the tissues. Researchers also plan to study additional HIV-positive patients who have undergone a bone marrow transplant.

Researchers point out that there are two key differences between the Brigham patients and the “Berlin patient,” a man who was functionally cured of HIV after a stem cell transplant. In the Berlin patient’s case, his donor was specifically chosen because the donor had a genetic mutation that resisted HIV. The Brigham patients’ bone marrow transplants were done without any thought to selecting an HIV-resistant donor. Second, the Berlin patient ceased anti-retroviral therapy after his transplant, while the Brigham patients have remained on anti-retroviral therapy.

Ref:

http://www.sciencedaily.com/releases/2012/07/120726153945.htm

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Men With Prostate Cancer More Likely to Die from Other Causes

Posted in Biological Networks, Gene Regulation and Evolution, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits on July 29, 2012| 3 Comments »

Reporter: Prabodh Kandala, PhD

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Word Cloud By Danielle Smolyar

Men diagnosed with prostate cancer are less likely to die from the disease than from largely preventable conditions such as heart disease, according to a new study from Harvard School of Public Health (HSPH). It is the largest study to date that looks at causes of death among men with prostate cancer, and suggests that encouraging healthy lifestyle changes should play an important role in prostate cancer management.

Prostate cancer is the most frequently diagnosed form of cancer, affecting one in six men during their lifetime. While incidence of prostate cancer has greatly increased in the United States, Sweden, and other Western countries in recent decades, the likelihood that a newly diagnosed man in these countries will die from the disease has declined. The researchers attribute this to the widespread use of the prostate-specific antigen (PSA) test, which has resulted in a higher proportion of men diagnosed with lower-risk forms of the disease.

The researchers examined causes of death among prostate cancer cases recorded in the U.S. Surveillance, Epidemiology, and End Results Program (over 490,000 men from 1973 to 2008) and the nationwide Swedish Cancer and Cause of Death registries (over 210,000 men from 1961 to 2008).

The results showed that during the study period, prostate cancer accounted for 52% of all reported deaths in Sweden and 30% of reported deaths in the United States among men with prostate cancer; however, only 35% of Swedish men and 16% of U.S. men diagnosed with prostate cancer died from this disease. In both populations, the risk of prostate cancer-specific death declined, while the risk of death from heart disease and non-prostate cancer remained constant. The five-year cumulative incidence of death from prostate cancer was 29% in Sweden and 11% in the United States.

Death rates from prostate cancer varied by age and calendar year of diagnosis, with the highest number of deaths from the disease among men diagnosed at older ages and those diagnosed in the earlier years of the surveys (especially in the years before the introduction of PSA screening).

Ref:

http://www.sciencedaily.com/releases/2012/07/120726135230.htm

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Discovery of New White Blood Cell Reveals Target for Better Vaccine Design

Posted in Biological Networks, Gene Regulation and Evolution, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits on July 29, 2012| Leave a Comment »

Reporter: Prabodh Kandala, PhD

Researchers in Newcastle and Singapore have identified a new type of white blood cell which activates a killing immune response to an external source — providing a new potential target for vaccines for conditions such as cancer or Hepatitis B.

Publishing in the journal Immunity, the team of researchers from Newcastle University in collaboration with A*STAR’s Singapore Immunology Network (SIgN) describe a new human tissue dendritic cell with cross-presenting function.

Dendritic cells (DCs) are a type of white blood cell that orchestrate our body’s immune responses to infectious agents such as bacteria and viruses, as well as cancer cells. They are also very important for eliciting the immune response generated by vaccines.

DCs kick start an immune response by presenting small fragments of molecules from micro-organisms such as bacteria and viruses, or from vaccines or tumours, called antigens on their surface. This leads to activation of another white blood cell subset called T cells, which specialise in killing cells and are crucial for eliminating cancerous or infected cells. Most cells are only able to present antigens from within themselves, and so will only elicit an immune response if they are infected themselves. Only a specialised subset of DCs is able to generate a response to an external source of antigen, for example bacteria, vaccines and tumours.

The identity of human tissue DCs that are capable of presenting external antigen to activate the cell-killing response by T cells — a process termed ‘cross-presentation’ — has remained a mystery. Their discovery, as revealed by this research, will help scientists to design better targeted vaccine strategies to treat cancer and infections such as Hepatitis B.

“These are the cells we need to be targeting for anti-cancer vaccines,” said Dr Muzlifah Haniffa, a Wellcome Trust Intermediate Fellow and Senior Clinical Lecturer at Newcastle University. “Our discovery offers an accessible, easily targetable system which makes the most of the natural ability of the cell.” The researchers also showed for the first time that dendritic cell subsets are conserved between species and have in effect created a map, facilitating the translation of mouse studies to the human immune system.

“The cross-species map is in effect a Rosetta stone that deciphers the language of mouse into human,” explains Matthew Collin, Professor of Haematology from Newcastle University.

In the paper the researchers describe how the cross-presenting DCs were first isolated from surplus plastic surgery skin which was digested to melt the gelatinous collagen to isolate the cells. This research will have significant impact on the design of vaccines and other targeted immunotherapies.

The Rosetta Stone of our immune system: Mapping Human and Mouse dendritic cells

The Newcastle University team in collaboration with A*STAR’s Singapore Immunology Network (SIgN) have for the first time ever aligned the dendritic cell subsets between mouse and humans allowing the accurate translation of mouse studies into the human model for the first time.

The researchers isolated the dendritic cells from human blood and skin and those from mouse blood, lung and liver. Using gene expression analysis, they identified gene signatures for each human dendritic cell subset. Mouse orthologues of these genes were identified and a computational analysis was performed to match subsets across species.

Abstract:

Dendritic cell (DC)-mediated cross-presentation of exogenous antigens acquired in the periphery is critical for the initiation of CD8⁺ T cell responses. Several DC subsets are described in human tissues but migratory cross-presenting DCs have not been isolated, despite their potential importance in immunity to pathogens, vaccines, and tumors and tolerance to self. Here, we identified a CD141^hi DC present in human interstitial dermis, liver, and lung that was distinct from the majority of CD1c⁺ and CD14⁺ tissue DCs and superior at cross-presenting soluble antigens. Cutaneous CD141^hi DCs were closely related to blood CD141⁺ DCs, and migratory counterparts were found among skin-draining lymph node DCs. Comparative transcriptomic analysis with mouse showed tissue DC subsets to be conserved between species and permitted close alignment of human and mouse DC subsets. These studies inform the rational design of targeted immunotherapies and facilitate translation of mouse functional DC biology to the human setting.

Ref:

http://www.sciencedaily.com/releases/2012/07/120728151028.htm

http://www.cell.com/immunity/retrieve/pii/S1074761312002798

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Tumor Cells’ Inner Workings Predict Cancer Progression

Posted in Biological Networks, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Genomics, Cancer Informatics, Cell Biology, Signaling & Cell Circuits, Gene Regulation, Genomic Expression, Hematology, Mutagenesis, Single Cell Genomics, Single-cell sequencing on July 29, 2012| Leave a Comment »

Reporter: Prabodh Kandala, PhD

Using a new assay method to study tumor cells, researchers at the University of California, San Diego School of Medicine and UC San Diego Moores Cancer Center have found evidence of clonal evolution in chronic lymphocytic leukemia (CLL). The assay method distinguishes features of leukemia cells that indicate whether the disease will be aggressive or slow-moving, a key factor in when and how patients are treated.

The findings are published in the July 26, 2012 First Edition online issue of Blood.

The progression of CLL is highly variable, dependent upon the rate and effects of accumulating monoclonal B cells in the blood, marrow, and lymphoid tissues. Some patients are symptom-free for years and do not require treatment, which involves the use of drugs that can cause significant side effects and are not curative. In other patients, however, CLL is relatively aggressive and demands therapeutic intervention soon after diagnosis.

“Our study shows that there may not be a sharp dividing line between the more aggressive and less aggressive forms of CLL,” said Thomas J. Kipps, MD, PhD, Evelyn and Edwin Tasch Chair in Cancer Research and senior author of the study. “Instead, it seems that over time the leukemia cells of patients with indolent disease begin to use genes similar to those that are generally used by CLL cells of patients with aggressive disease. In other words, prior to requiring therapy, the patterns of genes expressed by CLL cells appear to converge, regardless of whether or not the patient had aggressive versus indolent disease at diagnosis.”

Existing markers for aggressive or indolent disease are mostly fixed and have declining predictive value the longer the patient is from his or her initial diagnosis. When the blood sample is collected, these markers cannot reliably predict whether a CLL patient will need therapy soon, particularly when the patient has had the diagnosis of CLL for many years.

Kipps and colleagues studied thousands of genes, particularly those that code for proteins, in a group of 130 CLL patients with varying risks of disease progression. They identified 38 prognostic subnetworks of interacting genes and proteins that, at the time of sample collection, indicate the relative the aggressiveness of the disease and predict when the patient will require therapy. They confirmed their work using the method on two other, smaller CLL patient cohorts in Germany and Italy.

The subnetworks offer greater predictive value because they are based not on expression levels of individual genes or proteins, but on how they dynamically interact and change over time, influencing the course of the CLL and patient symptoms.

“In a sense, we looked at families rather than individuals,” said Kipps. “If you find in an interconnected family where most genes or proteins are expressed at higher levels, it becomes more likely that these genes and proteins have functional significance.”

He added that while the subnetworks abound in data, their complexity actually makes them easy to interpret and understand. “It’s like when you look out of a window and see the sky, clouds, trees, people, cars. You’re getting tremendous amounts of information that individually doesn’t tell you much. But when you look at the scene as a whole, you see patterns and networks. This work is similar. We’re taking all of the individual gene expression patterns and making sense of them as a whole. We’re more able to more clearly see how they control and regulate function.”

The findings help define how CLL — and perhaps other cancers — evolve over time, becoming more aggressive and deadly. “It’s as if each tumor has a clock which determines how frequently it may acquire the chance changes that make it behave more aggressively. Although the rates can vary, it appears that tumors march down similar pathways, which converge over time to a point where they become aggressive enough to require therapy.”

The study may alter how scientists think about CLL and how clinicians treat the disease: whether it is better to wait for later stages of the disease when tumor cells are more fragile and easier to kill, or treat early-stage indolent tumor cells aggressively, when they are fewer in number but harder to find and more resistant to therapy.

Abstract:

The clinical course of patients with chronic lymphocytic leukemia (CLL) is heterogeneous. Several prognostic factors have been identified that can stratify patients into groups that differ in their relative tendency for disease progression and/or survival. Here, we pursued a subnetwork-based analysis of gene expression profiles to discriminate between groups of patients with disparate risks for CLL progression. From an initial cohort of 130 patients, we identified 38 prognostic subnetworks that could predict the relative risk for disease progression requiring therapy from the time of sample collection, more accurately than established markers. The prognostic power of these subnetworks then was validated on two other cohorts of patients. We noted reduced divergence in gene expression between leukemia cells of CLL patients classified at diagnosis with aggressive versus indolent disease over time. The predictive subnetworks vary in levels of expression over time but exhibit increased similarity at later time points prior to therapy, suggesting that degenerate pathways apparently converge into common pathways that are associated with disease progression. As such, these results have implications for understanding cancer evolution and for the development of novel treatment strategies for patients with CLL.

Ref:

http://www.sciencedaily.com/releases/2012/07/120727154020.htm

http://bloodjournal.hematologylibrary.org/content/early/2012/07/26/blood-2012-03-416461

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Archive for July, 2012

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

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

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

Declines in Prostate Cancer Incidence After Changes in Screening Recommendations

David H. Howard, PhD

REFERENCES

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

The state of biosimilars in 2023

INCLUDED IN THIS TRENDLINE

Patent Disclosure Requirements

Intellectual Property Considerations

Keeping Trade Secrets Secret

Fine-Tuning Data Requirements

Determining Label Details

Embracing Biosimilars

Interchangeability and Exclusivity

Potential Cost Savings

Biosimilars and Follow-On Branded Biologics

Biosimilars Become Inevitable

Differences between Generic Drugs and Biosimilars

Laws and Regulatory Pathways for Drug Approval in the US

Law/Application Small-molecule Drug Biologics

Differences between small-molecule drugs and biologics

Product characteristics

Regulatory Landscape

Comparability Demonstration

Small-molecule Generics versus Biosimilars

Conclusion

REFERENCES

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Biosimilar Drugs by US Sales – not included in the Top 100 Drug List

U.S. Pharmacuetical Sales – 2012: Top 100 Drugs for Q1 2012 by Sales – Small Molecule Drugs (in green) and Biosimilars (in red)

Biosimilars Drugs by US Sales – not included in the Top 100 Drug List

2011 US Sales vs. 2008 US Sales (in Billions) for Top Selling Biologics

[i.e. Drug Name Enbrel, 2008 Sales $8.0B, Year approved 1998 , Indication RA]

Enbrel $8.0 1998 — RA, psoriatic arthritis, or ankylosing spondylitis indication

Remicade $7.9 1998 — RA & Chron’s Disease

Humira $7.3 2002 — treat rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, and plaque psoriasis

Rituxan $7.3 1997 — cancer medicines to treat non-Hodgkin’s lymphoma or chronic lymphocytic leukemia.

Herceptin $5.7 1998 — treat metastatic breast cancer that has progressed after treatment with other chemotherapy

Lantus $5.1 2000 — long-acting form of the hormone insulin.

Epogen/Procrit $5.1 1989 — Anemia, low RBC

Latest study shows anemia drugs Epogen, Aranesp and Procrit cause strokes, says FDA

Epogen / Procrit / Aranesp: The July 2012 News Report Which Tells Story Of Big Pharma Profits Over Patient Safety And Drug Efficacy

Procrit — (epoetin alfa) is a man-made form of a protein that helps your body produce red blood cells

Epogen — (epoetin alfa) is a man-made form of a protein that helps your body produce red blood cells

Neulasta $4.2 2002 — used to prevent neutropenia, a lack of certain white blood cells caused by receiving chemotherapy. stimulates the bone marrow and promotes the growth of white blood cells called neutrophils

Novolog $3.7 2000 — Insulin aspart is a fast-acting form of insulin. NovoLog is used to treat type 1 (insulin-dependent) diabetes in adults and children who are at least 2 years old. It is usually given together with a long-acting insulin.

Erbitux $3.6 2004 — used to treat cancers of the colon and rectum. It is also used to treat head and neck cancer.

Aranesp $3.2 2001 — Anemia, low RBC, (darbepoetin alfa) is a man-made form of a protein that helps your body produce red blood cells.

1/24/2011, Amgen boosts prices to offset Aranesp sales

Recombinate $2.9 1998 — Antihemophilic Factor VIII (Recombinant)

Lucentis $2.7 2006 intraocular injection. (ranibizumab injection) is a recombinant humanized IgG1 kappa isotype monoclonal antibody fragment designed for intraocular use. Ranibizumab binds to and inhibits the biologic activity of human vascular endothelial growth factor A (VEGF-A).

Novolin $2.5 1991 — Novolin R (insulin regular) is a short-acting form of human insulin, Diabetes, Type 1 Type 2

Novo Nordisk launches iPhone app Posted 17th September 2010, 15:11:54

Pegasys $2.0 2002 — (peginterferon alfa-2a) is made from human proteins that help the body fight viral infections. Pegasys is used to treat chronic hepatitis B or C. It is often used together with another medication called ribavirin (Copegus, Rebetol, RibaPak, Ribasphere, RibaTab).

Cerezyme $1.5 1994 — Gaucher disease and Fabrazyme for Fabry disease.

Tysabri $1.4 2004 — Multiple Sclerosis by Elan and Biogen

NovoSeven $1.4 1999 — Anti-fibrinolytics by Novo Nordisk —

Synagis $1.3 1998 — Generic Name: palivizumab Anti-virals by AstraZeneca

Betaseron $1.2 1993 — (interferon) is made from human proteins. Interferons help the body fight viral infections. Betaseron is used to treat relapsing multiple sclerosis (MS). Betaseron will not cure MS, it will only decrease the frequency of relapse symptoms.

Humulin $1.1 1992 Insulin Human by Eli Lilly

Conclusion

REFERENCES

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