Posts Tagged ‘clinical trial’

As noted in another post, I seem to have a refractory case of rheumatoid arthritis and have even been labeled as such by my rheumatologist. I’ve been on 16 different RA medications (see list bel0w) since being diagnosed in early 2009 (see https://rheumatoidarthritis.net/living/already-shot/). Some of these medications were taken in combination with one another. For example, methotrexate and Humira. All of these medications failed for a variety of reasons.

The latest drug on the heap of failed drugs is Kineret. I started injections starting Feb 7 after finally getting over a thrush infection which required two different anti-fungals to control. Within a day I started getting migraines and nausea. The migraines were present every day and increased in intensity to the point where I ended up taking migraine abortive medicines multiple times to knock them down. This happened after only having two significant migraine episodes the entire month of January. The nausea was primarily in the lower abdomen, got bad the second day, and increased to the point where it was waking me up in the middle of the night. I was not able to function well during the day. One evening I experienced sharp pains in the lower abdomen and also had some diarrhea periodically . Upon waking one morning, I just couldn’t stomach (pun intended) the thought of injecting Kineret and dealing with the migraines and nausea anymore. I contacted my rheumatologist and asked what to do. She stated, “I agree with stopping Kineret – thanks for trying. Let me chat with my partners to see what they think. There are several new drugs out for psoriatic arthritis that may have early data for RA too.

It’s hard to fathom untreated RA as the impact can be debilitating and disabling so treatment is needed. As my rheumatologist mentioned at the last appointment and in the recent message, it may be time to try something experimental and off label which would require insurance approval. Perhaps it’s time to investigate clinical trials as there are a host of drugs being tested for RA.

Rheumatoid Arthritis Drug  Duration  Reason for Stoping
Sulphasalazine oral

1 week

Allergic reaction – hives

Methotrexate oral and self-injection

2 years

Triggered migraines

Enbrel self-injection

5 months

Lack of efficacy

Meloxicam (Mobic) oral

3 weeks


Salsalate oral

3 weeks


Cimzia self-injection

5 months

Lack of efficacy

Humira self-injection

1.5 years

Reduced efficacy over time

Orencia infusion

1 year

Reduced efficacy over time

Imuran (azathioprine) oral

5 months

Gastric pain, nausea

Leflunomide (Arava) oral

5 months

Gastric pain, nausea, diarrhea

Actemra (tocilizumab) infusion

5 months

Raised cholesterol and triglycerides

Remicade (Infliximab) infusion

6 months

Triggered migraines

CellCept oral

6 months

Gastric pain, nausea

Rituxan (Rituxamab) infusion

2.5 years

Reduced efficacy over time, recurrent and serious infections

Xeljanz oral

3 months

Triggered migraines, gastric pain

Kineret (Anakinra) self- injection

1 week

Triggered migraines, nausea, diarrhea


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In an earlier post, I documented some of the new biologic medicines for RA in the development pipeline. There continues to be a constant stream of biologic drugs in research and development. But in the past few years, a new line of research led to the investigation of a set of molecules called kinases that are involved in the complex biological processes of RA. The development of kinase inhibitors is based on the theory that inhibition can slow down the production of inflammatory cytokines thereby controlling the disease processes. These processes are linked to the so-called JAK-STAT pathway that is being studied in numerous diseases.

Currently, there is only one kinase inhibitor approved for RA in the United States. Xeljanz, or tofacitinib, was developed and is marketed by Pfizer. The European Medicines Agency did not approve Xeljanz because of lack of efficacy and safety. Some European and Arab countries including Russia approved it.

Below is a list of some of the Kinase inhibitors currently in the development and trial pipeline. There are many others that died in the development pipeline.

Baricitinib by Eli Lilly and Incyte Corporation. Currently in Phase III clinical trials.

Fostamatinib by Rigel. In Phase II clinical trials. Efficacy is questioned.

CC-292 by Cellgene. In Phase II clinical trials.

PLX5622 by Plexxikon. In Phase I clinical trials.

AB494 by Abbvie. In Phase II clinical trials.

HM71224 by Hanmi. In Phase I clinical trials.

It remains to be seen whether or not JAK-STAT inhibitors will become a fruitful treatment option for those with rheumatoid arthritis.

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It is my thesis that the symptoms of rheumatoid arthritis, it’s real impact on people, and the lack of a cure and highly effective treatments is not being accurately portrayed in various forms of the press and media.

Pharmaceutical companies, primarily those with biological treatments for RA, have print and TV ads that show happy, active people easily engaged in physical activities such as cooking in the kitchen, playing soccer with children, and living carefree lifestyles. For example, watch this recent TV ad for Humira. The Enbrel ads featuring golf professional Phil Mickelson, which he takes for psoriatic arthritis (an autoimmune relative of RA), make it sound like he’s licked the disease and is better than ever. One review of these ads points out the caution that must be taken from this story. Nevermind the potential paid spokesperson issues involved in such ads. A recent article in USA Today portrayed a person with RA who is taking a current biological treatment and lives a very active physical lifestyle. The author used language that made it sound like the person was cured. The article received scathing reviews from numerous groups and people (read the posted comments) and the story was slightly modified although the main misrepresentations remain. A recent issue of the magazine Arthritis Today published by the large patient advocacy non-profit Arthritis Foundation features a cover story where a person with RA competes professionally as a triathlete. Upon seeing and reading such portrayals as those listed above, the general public would be prone to believe that rheumatoid arthritis is not that big of a deal.

It may be true that some RA patients do quite well due to low levels of disease activity, natural remission (a rarity), or symptoms well controlled by treatments. Biological treatments developed over the past 15-20 years resulted in many patients doing well and with rheumatologists indicating that they’ve seen a dramatic change in their practices. But the reality for a large proportion of RA patients is that they suffer everyday with uncontrolled or poorly controlled symptoms and do not adequately respond to treatment combinations. Up to 40% of RA patients are not helped by RA treatments or cannot continue treatments due to side effects (see this study by Rubbert-Roth and Finckh, 2009). One recent study reported that higher priced biologic drugs have had the same impact on time lost at work as older DMARD treatments. A meta-analysis (a statistical analysis of many studies) by Callhoff, et al (2013) demonstrated that the use of biologics help RA patients in physical functioning but that improvement was only seen in 50% of patients.

Disease remission is the goal of rheumatologists and advances in treatments help towards this goal (see this article by Collins in 2012). The currently accepted standard for remission as reported in Felson, et. al, 2011, p 581 is…

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)

These are stringent criteria and it would be difficult for many RA patients to meet this even on biological treatments. In 2011, Sokka et al stated that remission “…is not a common phenomenon in real life due to many hurdles.” And the rate of remission depends on the criteria used (Mäkinen, et al., 2005) with rates of remission ranging from 17-55% with only 13% reported as obtaining remission on all three sets of standards used. Many clinical trials are considered a success and the drug receives governmental approval for public use if the patients met older 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. It stands to reason that hundreds of thousands of RA patients in the U.S. alone do not meet “remission” criteria and that does not include the untold millions throughout the world.

The reality of unfettered disease activity is clearly evident in the RA patient online community. Read any of the discussion forums at the popular sites listed below and the norm will be discussions of patient suffering, unrelenting symptoms, lack of treatment efficacy, and side effects preventing them from taking prescribed treatments.

One could argue that these communities may be populated primarily by patients with uncontrolled disease activity and who are seeking help and relief. Even if this is the case, there are still tens or hundreds of thousands of patients who visit and post on these sites.

Read some of the most popular blogs written by people with RA and it will be clear RA is a constant companion that has had a great impact on life. Lene at the Seated View is in a wheel chair due to permanent joint damage and has been fighting RA symptoms for years. Carla at Carla’s Corner just had a knee replacement and this is not her first joint surgery due to RA. Mariah at her blog From This Point. Forward is changing medications once again due to unrelenting disease activity. All of these bloggers are taking some of the most current and sophisticated treatments for RA. These blogs and others (see this list) represent the patient voice of how the disease is really affecting their lives.

Could there be some people with rheumatoid arthritis who are in remission and leading physically active lives? Should these cases be celebrated? Can the stories of their lives be used to bring hope? The answer to all of these questions is a resounding yes. But it must be clear to medical professionals, pharmaceutical companies, government health funding agencies, researchers, non-profit agencies, advocacy groups, and the general public that such cases are the exception and not the norm. The vast majority of RA patients never reach clinical remission. Large portions of RA patients are not helped by the current RA treatments on the market or suffer side effects preventing them from continuing treatment.

Some organizations and individuals in the media may have underlying promotional and marketing purposes that drive their messages. But all I ask for is a balanced and realistic portrayal with integrity (see the journalistic code of ethics) in popular press and media. Anything other than that will only lead to misunderstanding, underrepresentation, and lack of advocacy for a disease that has no cure and whose current line of treatments that are not completely effective.

Postscript: Scott S commented on this article and left a wonderful quote from now deceased Deb Butterfield from her post titled Perceptions vs. Reality in Insulin-Free Times – “By showing the world only the happy face, and not the tragic disease beneath, we are endorsing the prevailing philosophy of tolerating, rather than curing, diabetes.”

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ACR 1I recently had the privilege to attend the annual meeting of the American College of Rheumatology. Considerable time was spent in the exhibit hall since, in addition to presenting a research paper, I was also volunteering at the booth of the Rheumatoid Patient Foundation.

The exhibit hall was overwhelming and the cavernous room was dominated by pharmaceutical companies. There were dozens of exhibits from large to small companies including, but not limited to, the following who provide many of the major biological treatments for RA:

ACR 2These pharmaceutical companies commanded the majority of the space and had professionally designed exhibits replete with multimedia presentations, large colorful signs and displays hanging from the ceiling, leather lounge chairs, espresso bars, snacks, colorful print materials, conference rooms, and an army of 20-30 sales representatives each. The rumor floating around was that these traveling exhibits cost upwards of $100,000 each in addition to the staff and other associated costs. They replace them every year. It is evident that the big pharmaceutical companies, especially those with expensive biological drugs on the market for RA, have vast amounts of funds to spend on sales and these exhibits. Based on this level of spending, it is obvious that this is big business and it is important for these companies to interact with the doctors and other health care providers who attend this conference in an effort to increase the sales of their drugs.

I enjoyed free espressos from Genentech/Roche each day – the manufacturer of my current RA medication Rituxan. One day while drinking my coffee and looking over research materials on Rituxan, a sales representative approached me obviously expecting me to be a doctor. I told her that I was a patient advocate who was actually taking Rituxan. She literally took a step backwards and told me that she was sorry and hoped I felt better. I laughed and said thanks and grabbed some print materials on clinical trail results and side effects. This awkward moment drove home the potential disconnect between the company sales force and patients. In spite of this brief and awkward interaction, the pharmaceutical companies must be commended for several things.

ACR 3Most of the research and development (R&D) behind these biological treatments for RA were paid for by the pharmaceutical companies. Oftentimes, the basic research, paid for by government or private foundation money, starts with a university-based researcher. These basic ideas lead to potential new treatments and the drug companies take over the onerous and lengthy task of developing and trying out new drugs. For biological drugs, this process may take years. And for every drug that makes it to market, there may be dozens that fail. Such development processes are extremely expensive and those costs are passed onto the patient in the cost of the drug. During the conference I was able to speak with several companies about RA treatments that are in Phase III Clinical trails (the last phase before seeking government approval). The concern is about who is going to pay for the R&D once pharmaceutical companies go over the so-called patent cliff in the next few years when their patents run out and they start to loose market share and profits.

Another patient benefit provided by the pharmaceutical companies for expensive biological treatments for RA are co-pay assistance plans. All of the companies listed above have such plans and they pay out millions of dollars each year helping patients be able afford treatments that can cost between $16,000 – $40,000 a year. This assistance, while extremely beneficial to those who need it, also demonstrates the large profit margins built into the “retail” costs of the drugs.

During the conference, I also met several consultants who are contracted by pharmaceutical companies to conduct research related to patient reactions and opinions about their products. While one may cynically infer that the companies are simply trying to increase their market share by pressuring the patients to ask for their drug, it was clear from the consultants that they genuinely want to increase the positive interactions between patients and the pharmaceutical companies in an effort to improve patient care and future drug development.

Yes, pharmaceutical companies are huge for-profit entities with a major goal of making money for shareholders. And the companies with major biological treatments for RA make enormous profits (Humira sales alone for the 4th quarter of 2012 were $2.7 billion). But they also bear the brunt of the R&D process, help with co-pays, and appear to seek patient interaction. As the patent cliff approaches, time will tell how it will impact these companies and the future of RA drug development.


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Stem Cells

A reader of this blog recently sent me information about a clinical trial involving stem cells as a treatment for rheumatoid arthritis. This prompted me to investigate further.

The American National Institutes of Health has a great descriptive website on stem cells. Stem cells are of interest to researchers since they are able to grow into a variety of different types of cells. They are proposed to be used for cell therapy – cells injected into a patient to impact a process, and regenerative therapy – cells used to regrow or repair damaged tissue. They are theorized to have great potential but that potential has been sought without much success for many years.

There is also a controversy with stem cells having to do with the harvesting of stem cells from embryonic tissue. This harvesting is typically done in vitro meaning that embryos are fertilized and grown in a lab. For those who believe life begins at conception, such harvesting is repugnant. The other type of stem cell harvesting is from adult tissue. Adult harvested stem cells can come from a variety of tissues.

The clinical trial in question is from a company called TiGenix which is a European cell therapy company based in Belgium. They only use adult stem cells harvested from fat or adipose tissue. They claim that their stem cells are less likely to result in immune system reactions resulting in rejection of the cells by the patient. Their stem cell Cx611 was used in a Phase II clinical trial to investigate safety and efficacy for rheumatoid arthritis.  One interesting aspect of this particular clinical trial is that they used patients with “refractory” RA – patients who failed to respond to biologic treatments. The patients receiving the stem cell treatment displayed lower disease activity than those receiving a placebo and safety data was positive. Here is a link to the press release and a link to a detailed presentation about the company’s foray into stem cell research for autoimmune diseases. The stem cells are theorized to impact the biological processes involved with RA induced inflammation and tissue damage. In summarizing the clinical trial, they stated,

“These results are remarkable, as they constitute the first ever signal of clinical activity of a cell therapy in RA. Moreover, this was achieved in the probably most refractory RA patient population ever evaluated in clinical studies.”

Check out this recent blog post from Diana at My RA Diary for a more detailed explanation of stem cell research and RA. In her post, she does an excellent job of outlining the potential of stem cells as a treatment. She cites research and posts some nice videos and diagrams.

It is exciting that researchers are investigating stem cell therapy as a potential treatment for RA. I suspect that we are years away from knowing if it will become a reality. But the Phase II clinical trial conducted in Europe is a promising step in the right direction.

Creative Commons Photo Credit: http://commons.wikimedia.org/wiki/File:Human_embryonic_stem_cells_only_A.png

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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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