Biosimilar

Biosimilars or Follow-on biologics are terms used to describe officially approved new versions of innovator biopharmaceutical products, following patent expiry.
Unlike the more common "small-molecule" drugs, biologics generally exhibit high molecular complexity, and may be quite sensitive to manufacturing process changes. The follow-on manufacturer does not have access to the originator's molecular clone and original cell bank, nor to the exact fermentation and purification process. Finally, nearly undetectable differences in impurities and/or breakdown products are known to have serious health implications. This has created a concern that copies of biologics might perform differently than the original branded version of the drug. However, similar concerns also apply to any production changes by the maker of the original branded version. So new versions of biologics are not authorized in the US or the European Union through the simplified procedures allowed for small molecule generics. In the EU a specially-adapted approval procedure has been authorized for certain protein drugs, termed "similar biological medicinal products". This procedure is based on a thorough demonstration of "comparability" of the "similar" product to an existing approved product. In the US the FDA has taken the position that new legislation will be required to address these concerns. Additional Congressional hearings have been held, but no legislation had been approved as of December 2007.

Recent FDA Actions Fuel Debate Over Copycat Biotech Drugs11-19-08 3:47 PM EST

NEW YORK -(Dow Jones)- The Food and Drug Administration's scrutiny of production changes by Genzyme Corp. (GENZ) and Amylin Pharmaceuticals Inc. ( AMLN) may signal a tougher stance in eventually evaluating generic versions of biologic drugs - should they ever become legal.

The market for so-called biosimilars could grow to as much as $200 billion a year by the middle of the next decade, as recently estimated by an industry executive, but their regulation will likely be more rigorous than that enjoyed by chemical counterparts. That scrutiny could make their development more difficult and expensive for generic drug makers, possibly hurting sales and forming a barrier to entry that allows only the largest companies to participate.
"This could be a concerted effort on the part of the FDA to draw a line in the sand in advance of a biosimilar pathway," said analyst Chris Raymond with Robert Baird & Co.
The FDA denied that it has changed its policies, saying that it "has had clear and consistent guidance about comparability since 1996." The agency wouldn't comment further.
No pathway for generic biologics exists in the U.S., but legislation to provide a pathway for generic versions is widely expected to be among President- elect Barack Obama's agenda. An official with Obama's transition team declined to comment on the issue.
Currently, generic drug makers can receive approval of copycat small-molecule drugs, like cholesterol-fighting statins, by showing they have the same active ingredient and the same action as the brand-name version, which allows the generics to depend on the original clinical trials and avoid having to pay for new ones.
Biotech drugs, made by culturing specially engineered organisms, are large proteins that are sometimes thousands of times bigger than small-molecule drugs. Their manufacturing makes them sensitive to minor changes in the process, potentially altering their complicated structures and even how they work in the body.
The biotech industry has long argued the complicated nature of the drugs makes it hard for a generic company to copy the drug, and expensive clinical trials should be used to prove similarity.
Earlier this year, the FDA decided that a version of Genzyme's Myozyme, to treat a rare enzyme disorder, produced on a larger scale had slight differences and had to be reviewed as a separate product with clinical data.
"I think what they have done with Myozyme is a pretty big departure," said Raymond, who notes that treating the larger-scale production as a separate brand was "unimaginable" until recently.
The FDA also recently requested more information on the comparability of Amylin Pharmaceuticals' Byetta LAR, an experimental once-weekly version of already approved twice-daily Byetta for diabetes. The issue is between batches of the drug made by partner Alkermes Inc. (ALKS) in its facility, used in previous clinical studies, and batches made on a commercial scale in Amylin's Ohio facility.
Barrier To Entry
The size of the generic biologics markets is unclear. In a 2007 report, Cowen & Co. estimated that U.S. sales of major biologics totaled $25 billion in 2006. Assuming lower prices, and limited penetration of generics, the firm estimates that the total generic revenue from those sales at $2 billion to $7 billion.
That differs greatly with the more recent projection of worldwide biosimilars sales of $200 billion by 2015 from Teva Pharmaceutical Industries Ltd.'s (TEVA) North American chief executive, Bill Marth.
But Raymond points to his own research that shows biosimilars of Amgen Inc.'s (AMGN) anemia treatments aren't being widely adopted in Europe yet.
Understandably, the biotech industry is hoping that the U.S. policies are tougher than in Europe, and it has long pushed for heavy scrutiny, citing the complexity of the products and processes.
The industry, led by the Biotechnology Industry Organization, advocates for clinical data requirements and fighting interchangeability, which allows the generic to be substituted for the branded drug, citing potential safety issues from imperfect drug copies.
While all parties involved are concerned about safety, those policies erect a number of hurdles for the generic companies.
Many observers expect biosimilars to require clinical data to some degree and be distinct products that must be marketed and specifically prescribed by physicians. That may make the drugs more expensive to develop and possibly less lucrative.
Furthermore, the scientific, manufacturing and marketing investment needed to enter such a market will likely allow only the biggest of the generic drug makers to take part, including Teva, Mylan Inc. (MYL) and Novartis AG (NVS).
"This is going to be a big thing. This is going to be very expensive, very intensive," Marth said. "I can't imagine somebody investing less than $1 billion and getting involved in this."
Teva has positioned itself to benefit from any regulatory pathway for biosimilars in the U.S., including its pending $7.46 billion acquisition of Barr Pharmaceuticals Inc. (BRL).
Evan McCulloch, a mutual fund manager with Franklin Templeton, believes that generic companies will have a tougher time selling generic biologics than small- molecule drugs.
He expects clinical trial requirements and companies having to sell biosimilars like a branded product using an expensive sales force, which is a new strategy for most generic companies. All of that could bode well for the biotechnology companies that would face sales pressure from generic competition.
"It is one thing when that drug goes generic and essentially disappears within three months," said McCulloch, referring to the situation seen with small- molecule drugs when generics enter the market, "and another thing entirely when you can bet that that drug is going to hold onto some of its revenues into perpetuity."
-By Thomas Gryta, Dow Jones Newswires; 201-938-2053; thomas.gryta@dowjones.com

Herbal medicine

I have been thought that the chinese traditional medicine from herbal is typically safe. However, recent discussions with my friends make me extremely nervous about the safety of the herbal medicine. The recent report (see below) is just one of the examples. The reason could be in multifold: 1) the safety is rarely tested in human trials; 2) counterfeit or shoddily made medications ; 3) the original herbal was now grown and harvested in total different climate/environment - the ingredient might be different from the original intended ingredient, some could be toxical. 4) contamination of the herbal raw materials.

China recalls hemorrhoid medicine
The Associated Press
Published: November 12, 2008
BEIJING: China's drug regulator ordered a nationwide recall of a hemorrhoid medicine Wednesday because of concerns it may cause liver problems.
The State Food and Drug Administration said in a statement on its Web site that it had ordered Vital Pharmaceutical Holdings Ltd., based in Sichuan Province, to stop producing Zhixue capsules and begin a nationwide recall. Twenty-one people around the country developed liver problems after taking the medicine in recent months.
"An obvious connection can be found between the hemorrhoid medicine and the liver damage after case analysis, but the cause of the adverse reactions remains unknown," the statement said.

China's pharmaceutical industry is highly lucrative but poorly regulated, resulting in some companies using fake or substandard ingredients. In recent years, a string of fatalities blamed on counterfeit or shoddily made medications has been reported.
Several herbal medicines have been recalled in recent months because of suspicions they have caused deaths, according to the official Xinhua News Agency.

The recalls come as China tries to reassure consumers over a scandal involving the spread of the industrial chemical melamine into the food chain, the latest incident to mar its already troubled product safety record.

Analysis Problems with Subgroup Analyses

Sub-grouping damages the balance obtained by randomization

• If the randomization is stratified for one factor (for example, disease severity), it will ensure the balance of the treatments inside the subgroups defined by that factor but not necessarily the balance of other prognostic factors (unless the subgroups are very large)
• When minimization is used, the balance for other stratification factors (eg., age category) inside the subgroups is not guaranteed.

Treatment comparisons within subgroups lack power

• the planned sample size N is large enough for detecting a specified difference in the WHOLE group
• Sub-grouping -> smaller sample size for each comparison -> lower power
• The statistical power to detect a treatment by subgroup interaction (ie. different treatment effects between subgroups) is usually very low

It is always possible to find subgroups in which the treatment effect is more extreme than the overall effect (data dredging)

• It is always possible to find a grouping of the sample such that the treatment effect is more pronounced in one subgroup and less pronounced in the other
• Indeed, the overall treatment effect is a sort of average of the subgroup treatment effects
• It is always possible to find a subgroup with a significant difference just by chance!

Subgroup anlaysis induce multiple testing problems

• Suppose you perform K tests, each of them at the alpha=0.05 significant level, the overall type I error rate (the risk of finding at least one spurious statistically significant result among the K tests) is alpha(overall) = 1-(1-alpha)^k
• The Bonferoni adjustment must be used to maintain the overall alpha close to 0.05: use alpha/K for each test

Improper subgroups

• Improper sugroups: subgroups of patients classified by an event measured after randomization and potentially affected by treatment - Response, means or survival comparisons to therapy, by compliance, by severity of side effects, or any factor not stratified for
• Inherent prognostic features inflence both the endpoint and the event
• Lead time bias: those who have the event early necessarily fall in the "poor" classification
• No causality relationship can be demonstrated

FDA Revises Process for Responding to Drug Applications

The following annoucement really makes sense. Previously, FDA could issue an "approvable" letter that could be very confusing. A product is 'approvable' based on efficacy, but can not be approved due to other safety concern.

http://www.fda.gov/bbs/topics/NEWS/2008/NEW01859.html

The U.S. Food and Drug Administration today announced that it is revising the way it communicates to drug companies when a marketing application cannot be approved as submitted.

Under new regulations that govern the drug approval process, FDA's Center for Drug Evaluation and Research (CDER) will no longer issue "approvable" or "not approvable" letters when a drug application is not approved. Instead, CDER will issue a "complete response" letter at the end of the review period to let a drug company know of the agency's decision on the application.
"These new regulations will help the FDA adopt a more consistent and neutral way of conveying information to a company when we cannot approve a drug application in its present form," said Janet Woodcock, M.D., director of the agency's Center for Drug Evaluation and Research (CDER). "Thorough and timely review of drug applications is a priority of the FDA, and these new processes will make our communications with sponsors of applications more consistent."
Taking the place of "approvable" and "not approvable" letters, a "complete response" letter will be issued to let a company know that the review period for a drug is complete and that the application is not yet ready for approval. The letter will describe specific deficiencies and, when possible, will outline recommended actions the applicant might take to get the application ready for approval.

Currently, when assessing new drug applications, the FDA can respond to a sponsor in one of three types of letters: an "approval" letter, meaning the drug has met agency standards for safety and efficacy and the drug can be marketed for sale in the United States; an "approvable" letter, which generally indicates that the drug can probably be approved at a later date provided that the applicant provides certain additional information or makes specified changes (such as to labeling); or a "not approvable" letter, meaning the application has deficiencies generally requiring the submission of substantial additional data before the application can be approved.
"Complete response" letters are already used to respond to companies that submit biologic license applications. The process for drugs and biologics will be consistent under the new regulations.

The revision should not affect the overall time it takes the FDA to review new or generic drug applications or biologic license applications. These changes, which will become effective on Aug. 11, 2008, are not expected to directly affect consumers.
In July 2004, the FDA issued a proposed rule on these topics. At that time the agency asked for comments on the proposal. Today's final rule addresses comments submitted to the agency.
For more information, see:

Link to the Complete Response Final Rulehttp://www.fda.gov/cder/regulatory/complete_response_FR/default.htm
Link to the drug approval process pagehttp://www.fda.gov/fdac/special/testtubetopatient/default.htm

PRO, CRO, and Laboratory tests / device measurements

In an article by Willke et al (Controlled Clinical Trials, 25, 2004), the study endpoints were classified as three major categories. Endpoints were classified into the following three major categories, and the presence or absence of each of these categories was noted for each product reviewed. Each product may have employed one, two, or all three types of endpoints:

• Laboratory tests and device measurements,
• Clinician-reported outcomes (CROs)
• Patient-reported outcomes (PROs).
  

Laboratory and device measurements included highly objective typically numerical measures often performed by machine.

Clinician-reported outcomes included those that might be considered traditional endpoints, either observed by the physician (e.g., cure of infection and absence of lesions) or requiring interpretation by the physician (e.g., radiologic results and tumor response). In addition, CROs included both formal and informal scales completed by the physician using information about the patient. CROs requiring patient input are distinguished from clinicianadministered PROs in that the former requires clinician judgment or interpretation when recording answers, while the latter involves recording precise, unmodified patient responses to prespecified questions.

Finally, endpoints classified as patient-reported outcomes included formal health-related
quality of life measures and any other endpoint that was primarily based on a direct patient report. PROs categorized as "formal" scales are those multiitem questionnaires that have a well-defined standardized format, well-documented procedures for administration and scoring, demonstrated reliability and validity, and some guidelines for interpretation of scores. Other PROs included informal symptom scales, patient global assessments, or visual analog scales, as well as patientreported endpoints recorded in event logs (e.g., specific events). In some cases, nonclinician proxies reported the outcome from the perspective of the patient (e.g., when vaccines were tested in infants); these endpoints were considered patient-reported.

Declaration of Helsinki and FDA

The newly released Declaration of Helsinki was issued by the 59th World Medical Association General Assembly in October 2008. This document details ethical principles for medical research involving human subjects.

Section 19 requiring every clinical trial to be registered before recruitment of the first subject. Also note Section 30 on the obligation to make public the results of research on human subjects and requirements for publications. The additional contents are in line with the recent push for registry of the clinical studies and publication of the clinical trial results.

http://www.wma.net/e/policy/pdf/17c.pdf
http://www.wma.net/e/index.htm
http://en.wikipedia.org/wiki/Declaration_of_Helsinki

However, the FDA is moving away form the Helsinki accords because of what it says about placebo. The following two links discussed this issue.
http://www.socialmedicine.org/2008/06/01/ethics/fda-abandons-declaration-of-helsinki-for-international-clinical-trials/
In 21 CFR 312, "Human Subject Protection; Foreign Clinical Studies Not Conducted Under an Investigational New Drug Application- Notice of Final Rule", FDA states
" The final rule replaces the requirement that these studies be conducted in accordance with ethical principles stated in the Declaration of Helsinki (Declaration) issued by the World Medical
Association (WMA), specifically the 1989 version (1989 Declaration), with a requirement that the studies be conducted in accordance with good clinical practice (GCP), including review and approval by an independent ethics committee (IEC)."

A article on EMBO report (7(7), 2006) titled "The Battle of Helsinki" is worth to read.

North Carolina's Triangle Business Journal (2/19, Gallagher) reports that "the study also questions the decision by the US Food and Drug Administration in 2008 to abandon the Declaration of Helsinki, a set of standards adopted by the World Medical Association in 1984 that required trials to compare new drugs with the most effective alternative." The Food and Drug Administration "dropped the Helsinki standards in favor of the policy of Good Clinical Practice adopted by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. That policy, which allows drug manufacturers to compare the results of the new drug with those of a placebo, is considered by some to be less stringent than the Declaration of Helsinki."