Posts Tagged ‘FDA’

On March 6, 2015 the Food and Drug Administration (FDA) approved the first biosimilar drug for use by patients in the United States (see FDA press release). The drug called Zarxio (filgrastim-sndz) is produced by Sandoz and is similar to Amgen’s Neupogen (filgrastim). Both are approved to treat certain kinds of cancers and bone marrow transplants.

Biologic medicines come from living organisms. They are different from chemical medicines in that they contain large and delicate biological molecules such as proteins, must be injected or infused since stomach acids would damage the molecules, and are usually much more expensive than chemical medicines due to development and complicated production costs. Given the high development costs associated with biologics, they are given an extended patent length of 12 years in the United States. When a chemical drug looses its patent protection, companies produce generics that are exact chemical matches. Generics are widely used and are much cheaper than the original drug. Given the complexity of biologics, exact chemical matches are replaced with scientific equivalency meaning that the biologic is similar in action but not exactly the same – thus the name “biosimilar” being used for these drugs (Entine, 2012).1

Some of the most popular RA biologic medicines stand to loose patent protection in the United States in next few years.

Read the rest of the article at http://rheumatoidarthritis.net/news/fda-approves-first-biosimilar-drug-whats-next-for-ra/.


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My right elbow has been giving me troubles for over a year now and my rheumatologist referred me to an orthopedic surgeon who specializes in hands and elbows. An MRI revealed a 50% tear in a tendon. Other parts of the elbow exhibit pain. In fact, the left elbow also displays the same symptoms but to a lesser extent probably due to the fact that I am right handed. The orthopedic doctor knows about my struggles with RA and my history with soft tissue damage. In fact, he works in the same clinic with the surgeon who conducted three surgeries on my ankles.

A bevy of conservative treatments were prescribed starting with rest and immobilization with splints designed to prevent movement of the tendon. After that failed to help, a cortisone injection was done. The doctor also used the needle to aggravate the tissue in the joint in order to stimulate a healing process by increasing blood flow to the region. Needless to say, excruciating pain was experienced for the next 24 hours but after that, the steroid provided some relief…for about 1 month after which time the pain returned. Occupational therapy was then prescribed. Occupational therapists (OT) tend to focus on the arm from the elbow down to the hand and they engage in treatments similar to physical therapists. Treatments included heat and transcutaneous electrical nerve stimulation (TENS), gentle stretching exercises, and continued use of immobilization with splints. The goal was to move into more rigorous strength building exercises. But this goal was never met as the pain only became worse. After several months of OT, the therapist made the decision that things were getting worse and indicated that I need to return to the surgeon to determine next steps. At about this time, severe neck problems were popping up and the orthopedic surgeon and I both agreed that priority needed to be given to the neck. The past six months were devoted to recovering from neck surgery.

The elbow continued to cause problems and it came to the point where use was difficult and pain was constant so I returned to the orthopedic surgeon. He said that surgery to repair the torn tendon and its attachment point to the bone would be the next option. But before doing that, he wanted to try one more, last ditch strategy – a platelet-rich plasma injection or PRP. He admitted that the research was sketchy and that it was not an FDA or insurance approved treatment. I would be required to pay for it out of pocket and the cost will be about $300. His argument is that in spite of the lack of experimental research on its effectiveness, there is clinic evidence, it is relatively inexpensive, and it is not as invasive as surgery. He did give me a choice between PRP and surgery but his comments were, “If it were me, I would do this first before having surgery.”

In PRP, a patient’s blood is drawn, platelets are separated from other blood components, and the concentrated solution is injected into a joint that has tissue damage in an effort to jump-start a healing process.[1] The theory is that growth factors contained in the platelets are able to help damaged tissue heal. It has been applied to tendon areas like the Achilles and elbow where there is a lack of blood low and healing is difficult. This approach is quite popular with professional athletes but clinical trails show mixed results (Harmon & Rao, 2013).[2]

In medical practice, there is a range of possible qualities of treatments. Balshem et al (2010) categorizes the ranges from very low quality to high quality evidence.[3] The approval of drugs would rate as high quality evidence. At the lowest end of the evidence quality continuum would be treatments that have little or conflicting evidence. Platelet-rich plasma would rank at the lowest end. This is why the FDA and insurance companies won’t approve it. There is even less research about PRP and rheumatoid arthritis. A search of research studies specific to RA revealed one study conducted on pigs[4] and another conducted in 1989 on knees of RA patients.[5] Never provided sufficient evidence documenting the effectiveness of PRP for rheumatoid arthritis.

Given the lack of evidence, I remain quite skeptical about PRP but am willing to give it a shot (pun intended) in order to avoid surgery.

[1] http://orthoinfo.aaos.org/topic.cfm?topic=A00648

[2] http://www.ncbi.nlm.nih.gov/pubmed/24319241

[3] http://www.jclinepi.com/article/S0895-4356(10)00332-X/abstract

[4] http://onlinelibrary.wiley.com/doi/10.1002/art.30547/full

[5] http://link.springer.com/article/10.1007/BF00270285#page-1

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For thousands of years and across many cultures, marijuana, or cannabis, was touted as possessing medicinal properties. And its use for both medicinal and recreational purposes is gaining in popularity in recent times. Some activists are advocating its use for rheumatoid arthritis. My desire is that RA patients will carefully consider all treatments for their disease. The topic must be raised in public forums and from scientific perspectives. I realize that this article will likely bring about a slate of responses, both for and against. Such is a nature of controversial topics…

…read the rest of this post at http://rheumatoidarthritis.net/living/medical-marijuana-a-viable-option-for-the-treatment-of-ra/

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Etanercept (Enbrel) structure

Etanercept (Enbrel) structure (Photo credit: Wikipedia)

It was recently announced that Etacept was being launched in India by the generic drug company Cipla as a “biosimilar” to Enbrel (Etanercept). This new biological drug is designed to treat rheumatoid arthritis and other rheumatic conditions and is being manufactured by China-based Shanghai CP Guojian Pharmaceutical Company Ltd. It is supposed to cost 30% less than Enbrel. The approval of this biosimilar in India is not without controversy as biotechnology companies are complaining that Cipla did not follow the standards for approval (see this article).

In the United States, patent exclusivity for biological drugs is set at 12 years. This is designed to protect the expensive and time consuming processes involved in developing and testing these complex biological treatments. However, there is an approaching “patent cliff” (see this excellent article on biosimilars). Of all biologicals used for a variety of diseases, Humira, Enbrel, Remicade, and Rituxan are among the most profitable biologicals on the market. These drugs will lose their patent protection in the next few years. Once the patent cliff is reached, large pharmaceutical companies stand to lose billions of dollars in sales (see this article). The Biologics Price Competition and Innovation Act (BPCIA) of 2009 was built into the Patient Protection and Affordable Care Act (“Obamacare”) and is designed to speed up the process of approval for biosimilars. Large generic drug manufacturers are beginning to ramp up to enter the biosimilar market

Over the next few years, we will likely begin to see a slew of biosimilars for RA begin to hit the market worldwide. The potential savings to patients and insurance companies will competitively drive the market (see this article). Decisions about starting or switching to the biosimilars will need to be made. The efficacy and safety of these look-alike drugs will be questioned. This will also drive large pharmaceutical drug companies to research and develop new drugs for RA in order to maintain a competitive edge.

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There are many choices of drugs when treating RA including numerous DMARDS and biologicals. Most of the currently used RA drugs are relatively new being developed and marketed in the past few years. In an earlier post, I documented that there are dozens of new RA drugs in the development pipeline. Do you wonder where all these new drugs for RA come from? Who develops them? How are they proven to work? What’s the difference between small and large molecule drugs? What are biosimilars? How are new drugs approved for use? How are they marketed? Who pays for the development?

If you want to learn more about these topics, I invite you to join me by taking a short online course from the University of California San Diego called

Drug Discovery, Development & Commercialization

The instructors are Williams S. Ettouati and Joseph D. Ma who are professors of pharmacy at UC San Diego.

MOOC_-_Massive_Open_Online_Course_logo.svgThis course is what is called a MOOC which stands for Massive Open Online Course.  Massive – Many people from a variety of backgrounds will be in the course, sometimes thousands. There are already over 12,000 people registered for this course! Open – It’s open to anyone and they are free. Online – All of the course activities and information are totally online. These courses are more about connecting and collaborating rather than taking a passive traditional course. MOOCs are rapidly becoming a popular way to take a course from a leading university taught by well known experts in the field. Check out this video and resource if you want to know more about MOOCs. This course is delivered through Coursera which is a leading provider of MOOCs by universities all over the world.

Join me if you want to learn more about this topic which is closely related to RA drugs. This particular course starts April 19 and is 9 weeks long. You’ll probably spend a couple of hours a week reading material and interacting with students. Let me know by sending me an email if you plan to take the course and I’ll look for you online. You can register through the Coursea website.

MOOC image By Andybulle [GFDL (http://www.gnu.org/copyleft/fdl.html) or CC-BY-SA-3.0 (http://creativecommons.org/licenses/by-sa/3.0)%5D, via Wikimedia Commons

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My wife used to call me a science geek and it’s true. In high school and college, I fell in love with science as a way to explain the natural world. Since being thrown headfirst into the world of rheumatoid arthritis, it’s natural for me to apply this “geekiness” to all aspects of the disease both globally and personally.

A brief primer in research methods is necessary in order to understand the issues involved. Professor Trochim at Cornell University has an excellent website on research (http://www.socialresearchmethods.net/kb/index.php). He points out that research is based on some basic principles of logic and philosophy. First, it is empirical meaning that it is data-based. For example, if a pharmaceutical company is testing a new drug for efficacy in a clinical trial, they will administer the drug to patients and collect information (data) on the impact of the drug on symptoms. For RA, this may include the number of tender and swollen joints, bone erosion as viewed by x-rays or MRIs, pain level on a scale of 1-10, morning stiffness in minutes, etc.

Second, research is based on probabilities meaning, “the chance that a particular event (or set of events) will occur expressed on a linear scale from 0 (impossibility) to 1 (certainty), also expressed as a percentage between 0 and 100%.”[i]  In order to increase the probability, large sample sizes must be used and careful measurements must be made. Yet, scientists can never be 100% certain about the data and observations they collect. Using the drug example again, results from a clinical trial can be used to argue that the drug helps some people but the scientists can never be 100% certain that it’s the drug helping the patients or some other factor.

Thirdly, science attempts to find cause and effect relationships – one factor causes an impact on another. This is usually framed in the form of a research question. For example, Does a drug reduce symptoms of a disease? As Professor Trochim says, “Experimental designs are often touted as the most rigorous of all research designs or, as the gold standard against which all other designs are judged.”[ii]

Experimental designs are required for drug clinical trials. Such trials usually include large numbers of patients in order to increase probabilities. Studies include a control group which includes a group of patients who do not receive the medicine being studied – a placebo. In a RA related study, the placebo group may receive a sugar pill or a saline solution. They are also usually double blind meaning that the patient and the scientists do not know what treatment the patients are receiving in order to minimize bias.

enbrel resultsLet’s take an example from a popular biological treatment for RA – Enbrel. The drug company, Amgen, ran multiple clinical trials with many RA patients and collected data on multiple symptoms. They report,  “A higher percentage of patients treated with Enbrel and Enbrel in combination with MTX achieved ACR 20, ACR 50, and ACR 70 responses and Major Clinical Responses than in the comparison groups.”[iii]  A graph is used to present some of the results (see figure).[iv] Clearly those patients who received Enbrel had fewer symptoms than the placebo group and this was the basis for the approval of this drug by the U.S. Food and Drug Administration (FDA). However, some caution must be used when interpreting the results. Not all patients who received Enbrel responded to the treatment. Those who did respond still had symptoms of RA but to a lesser extent. These results were only for six months and it says nothing about the long term impact of the drug. Side effects, either short term or long term, are not reported by this graph (side effects are reported separately).

Understanding the processes of research helps patients understand the benefits and limitations of treatments.  This also leads to personal application. I once had a doctor tell me that he only wants to change one medication at a time in order to determine cause and effect. That’s a smart move in order to find out what each drug is doing. In some ways, each patient is a mini experiment trying to find out what treatments impact symptoms. But the limitation is that it is a sample size of one…hardly enough to make generalizations to other patients since everyone responds differently. I also read various patient experiences on website discussion boards and drug review sites. While such individual reactions may be interesting and worthwhile for gaining perspective, they must be interpreted with caution as they may not based on sound scientific methods and sample sizes. Patients must understand the limitations of such discussions. Just because a medication didn’t work for me or had extreme side effects does not mean it won’t work for someone else. Sometimes, too much negative information ends up on such sites driving patients to fear resulting in refusal to take medications.

Patients must understand the processes of research and be good consumers of the plethora of information that comes our way.

[i] http://mathworld.wolfram.com/Probability.html

[ii] http://www.socialresearchmethods.net/kb/desexper.php

[iii] http://pi.amgen.com/united_states/enbrel/derm/enbrel_pi.pdf

[iv] http://pi.amgen.com/united_states/enbrel/derm/enbrel_pi.pdf

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8101257735_8338a4603dIn an article recently published in USA Today, the author discusses the possibility of remission in rheumatoid arthritis. It presents a case of a women who takes Enbrel and methotrexate and is living an active lifestyle. The advent of biological treatments for RA in the last 10-15 years has indeed made a huge impact on RA patients. In fact, my rheumatologist told me that she’s seen things change dramatically in her practice and patients. For this I am truly glad.

However, this author fails to accurately report the whole story. These amazing and expensive treatments are just that…they treat but don’t cure the disease. Remission is an elusive and perhaps temporary state. In 2011, the American College of Rheumatology (ACR) in collaboration with the European League Against Rheumatism (EULAR), updated the criteria for remission. Using the ubiquitous measure of disease activity, the DAS28 ACR-EULAR, the new criteria are as follows:

At any time point, patient must satisfy all of the following:
Tender joint count - equal or less than 1
Swollen joint count – equal or less than1
C-reactive protein – equal or less than 1 mg/dl
Patient global assessment – equal or less than 1 (on a 0–10 scale)

(Felson, et. al, 2011, p 581)

That’s much more strict than the previous criteria and it would be difficult for many RA patients to meet this even on biological treatments. These new criteria are to be used for clinical trials for RA medications to be approved by the FDA. In fact, many previous clinical trials are considered a success if the patients met the old ACR criteria oftentimes reported as ACR 20, ACR 50, or ACR 70 meaning that the patient reported a 20%, 50%, or 70% improvement in symptoms. In most clinical trails, the majority of patients don’t meet the ACR 70 (see this package insert which reports clinical study results). This is not remission, only an improvement in symptoms.

In the USA Today article, it was reported that one study with Enbrel and methotrexate combination resulted “more than 75% of those treated with Enbrel and Methotrexate experienced no progression of joint damage after three years.” That is one study, for one drug combination of which there are many, and was likely based on the less stringent ACR criteria used before 2011. Even if this data was applicable to all RA patients and medication combinations, that would still leave 25% of 1.5 million RA patients in the U.S. alone who do not meet “remission”. That is 375,000 patients! And that does not include the untold millions throughout the world.

Finally, there is the issue of failure of biological treatments. It is well documented that some patients don’t respond to biological treatments for a variety of reasons. In a recent research review, the researchers stated,

“However, about 20% to 40% of patients treated with a TNF inhibitor fail to achieve a 20% improvement in American College of Rheumatology criteria, and more lose response over time (secondary failure or acquired therapeutic resistance) or experience adverse events following treatment with a TNF inhibitor.”

This failure from a large proportion of RA patients can be from lack of initial response, loss in response over time as the patient builds antibodies against the biological treatment proteins, or from severe side effects.

While I am so thankful for the advent of biological treatments and the huge impact that they have on RA patients, we must remain cognizant of the reality that these treatments are not cures, they don’t work for many patients, may fail to work over time, and they may give severe side effects. For these reasons, we must treat this chronic illness as not yet defeated or cured and scientific research must continue.

Postscript December 23, 2012…after many people commented on the article and sent letters to the author and editor, some changes were made to the title and article text. However, the author still does not scientifically define RA remission using current ACR criteria, does not detail the many other RA treatments, and avoids the topic of the large proportion of patients who do not respond to biologicals or fail to respond over time.  

Creative Commons Photo Credit: http://www.flickr.com/photos/meganschuirmann/8101257735/

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