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From time to time, we’re asked if there are any clinical studies regarding Inflammation Therapy (IT) or if there are any statistics regarding the efficacy of this treatment.

Use of this type of treatment began in 2001 and later expanded through Internet communities who accessed various websites. Members, with the help of their personal physicians, trialed the intervention and reported their results.

Autoimmunity Research, Inc (also known as ARF) state they maintain close ties with the FDA and report they're conducting a clinical study. They refer to one of their websites as a 'study site' and all members who post anecdotal reports on the message boards there (regardless of frequency) are said to belong to a cohort of active subjects.

Although ARF's approach has some of the earmarks of a FDA Phase II clinical trial, it does not meet important FDA clinical study standards for the following reasons:

• Not operating under an approved Investigational New Drug (IND) application

• Not being conducted under the guidance of Institutional Review Boards or a Data, Safety and Monitoring Board

• Not being conducted in accordance with FDA rules on human studies (e.g. adherence to the principles of good clinical practices, including adequate human subject protection)

• Not obtaining informed consent of participants

• Not listed or registered (according to law) at http://www.clinicaltrials.gov/

Statistics

The only statistics available on this type of treatment were gleaned from a retrospective questionnaire completed by a select group of 100 members of the ARF website community. This limited, subjective data was presented at a 2008 conference and is often referred to as definitive. It’s worthwhile noting also that in a valid study, such a questionnaire is considered an intervention that negates the results.

Unsubstantiated claims

Statements citing statistics used to support current therapy policies at ARF websites are not accurate. For example, the claim is made that none of the “more than 1000 seriously ill subjects” monitored (for 2-8 years) have needed dialysis and that even though their eGFR frequently measured “in the 20s and 30s for months at a time”, all patients have successfully managed seriously abnormal lab results by increasing Benicar. In reality, patients whose lab work did not improve with the use of high-dose Benicar, or improved with less Benicar, stopped reporting (e.g., LadygoDarker) and were lost to follow up.

It would be helpful if those who claim they’re cured or recovered would publish lab work or other hard data (imaging reports, pulmonary function tests, dexa scans, etc.) to add weight to their anecdotal reports.

Obstacles to a study

Based on anecdotal reports of Inflammation Therapy success, a clinical trial would be appropriate to make this effective treatment more available to the community. FDA designation of Minocycline and Clindamycin as orphan drugs for the treatment of sarcoidosis opened the door to an approved clinical study but there are many obstacles, including:

• The medical community does not recognize the messages posted at www.marshallprotocol.com as a valid Phase II clinical trial.

• The scientific community does not yet accept the intracellular pathogenesis of chronic inflammation.

• The lack of funds (funds are allocated to recognized research institutions).

Although the Food and Drug Administration approved Benicar at the 40mg dosage once or twice a day for hypertension it has not yet been submitted for approval at higher doses because the prospective clinical trials that are required for FDA approval need to be funded at the cost of tens of millions of dollars. In the absence of such a current scientific clinical trial, medical journals tend not to be interested in "anecdotal" reports of therapeutic successes.

While a Phase III study isn’t necessary to use the already approved medications of IT, publication of an approved clinical trial would assist patients who are having difficulty finding Healthcare Providers because they who require this level of proof.

Orthodox researchers and clinicians insist on double-blind, placebo-controlled, randomized clinical trials of high statistical significance, approved by institutional review groups, and published in respected peer-reviewed journals. These are high hurdles to be surmounted.

Inflammation Therapy is based on a theory of chronic disease. We fully expect the hypothesis to be tested in time by academic scientists, and to have clinical trials and experiments done in human populations.

Background

Historically, medical therapy has been marketed without scientific proof of safety or efficacy. The Drug Amendment of 1962, passed in the wake of the thalidomide tragedy, requires manufacturers to prove to the FDA that products are safe & effective, prior to marketing. However, medications remain in use today that have not been subjected to this higher standard. Regarding prednisone, for example, the standard treatment for sarcoidosis, Dr. Om Sharma, considered an expert, states, "It is clear that there may never be an ideal prospective, double-blind, controlled study.” (of the use of prednisone in sarcoidosis)

Evidence-based medicine

Because today's doctors and patients demand proof of safety and efficacy, a system of clinical trials has been set up. This system is commonly referred to as evidenced-based medicine (EBM). Contrary to popular belief, evidence-based medicine is not restricted to randomized trials. According to Sacket et. al. in a 1996 BMJ article, "Evidence-based medicine involves tracking down the best external evidence, with which to answer our clinical questions....If no randomized trial has been carried out, for our patient's predicament, we follow the trail to the next best external evidence, and work from there."

EBM is the conscientious, explicit, and judicious use of current best evidence in making clinical decisions about the care of individual patients. Evidence is not always derived from well-executed scientific studies. Often, scientific evidence to support EBM has had to be supplemented by professional consensus.

"Evidence-based medicine is the doctor's judgment, the patient's values, and the evidence. No one of those trumps the others."
David S. Jevsevar, MD, MBA,
Chair of the AAOS Committee on Evidence-Based Quality and Value

Clinical Studies

Clinical studies assess whether the new therapy is better than standard therapy or compare the efficacy of two standard therapies. They also distinguish a therapy's effect from other influences such as a spontaneous change in disease progression or the effect of a placebo.

The Food and Drug Administration is the US regulatory agency for medical products and any product sold as a medication must first have FDA approval. All new medications require clinical trials prior to FDA approval. The medications used with Inflammation Therapy are all approved by the FDA for other uses.

Approval for a specific purpose is not essential, but it lends credibility for that use. Off-label use (i.e. using a medication for something other than the FDA-approved use) is quite common. The use of olmesartan medoxomil (Benicar) for inflammation rather than hypertension was originally a sticking point for many Healthcare Providers, but more recent studies support the anti-inflammatory properties of angiotensin receptor blockers. http://circ.ahajournals.org/cgi/content/full/110/9/1103

FDA regulatory oversight mandates that clinical trials be conducted under an approved Investigational New Drug (IND) application and under the guidance of Institutional Review Boards or a Data, Safety and Monitoring Board. These are independent committees comprised of doctors, statisticians, community advocates and other experts who approve and periodically review the research to ensure that a clinical trial is ethical and to ensure that the rights of study participants are protected. Other ethical considerations are important when conducting a clinical trial. It must be in accord with FDA rules on human studies and with informed consent of participants.

The rights of individuals participating in clinical trials must take precedence over the potential benefit to society as a whole. Physicians conducting clinical trials must ensure that they do no harm to the patients in their study. Randomized trials are restricted to those therapies that have shown potential usefulness in systematic preclinical studies. And studies must be peer reviewed and/or reviewed by government regulators.

Clinical trials are funded by pharmaceutical or biotech companies and product manufacturers whose business it is to develop and commercialize therapies. Government regulators such as the National Institutes of Health, Department of Defense and the Veterans’ Administration are other major sources of funding. Patients, patient organizations and foundations fund studies, often because they want faster access to cutting-edge treatments. Hospitals, universities, researchers and institutions view trials as a source of income and prestige and may use private and/or government funding.

There are four phases of clinical trials:

  • Phase I trials test a therapy for the first time and study a small number of healthy subjects.
  • Phase II trials test efficacy and safety on a limited number of diseased patients, to establish safe and optimal doses.
  • Phase III trials compare a new therapy to other therapies or to a placebo. They are administered under real-world conditions to obtain proof of safety and efficacy.
  • Phase IV trials follow up already marketed therapies.

Clinical study design

Clinical studies are designed in a variety of ways.

A prospective study looks forward in time, as opposed to a retrospective that looks at historical data. Subjects are divided into groups and observed over a length of time. This may also be referred to as an observational study.

In an open study, also called open-label, the researcher and subjects know the full details of the treatment.

In a randomized study, patients are assigned to one arm of the study in a random manner.

A controlled study compares subjects receiving the new therapy to those receiving a placebo or a standard therapy.

There are several types of blinded studies. In a single-blind trial, the researcher knows the details of the treatment but the patient does not. This is intended to eliminate the placebo effect.

In a double-blind trial, neither the patient nor the investigator knows the details of the treatment. This is intended to reduce influence and, thus, bias.

In a triple-blind trial none of the participants - the subject, the investigator, the pharmacist or statistician - knows who is getting which treatment. This study has the least bias.

There are many elements to a successful trial. The essential seven include:

1. The rationale for the trial, or reasons it should be carried out
2. The design, which should compare different treatments
3. The inclusion and exclusion criteria, which determine which patients should enter the trial
4. The use of randomization or bias control measures
5. The number of patients to be tested in order to produce clear results
6. The carefully defined outcome events (that is, measures of how well patients recover)
7. The analysis of the data

Trials that are randomized and controlled are considered the most reliable and therefore, the “gold standard”.

The goals of a randomized, controlled trial are:

• to remove any factors which might skew the results
• to include control groups which are undergoing the same routine but are either:

o receiving a placebo
o receiving the standard treatment or
o receiving no treatment

Difficulties designing a study of Inflammation Therapy

The main disadvantage of Randomized Controlled Trials (RCT) is they are very expensive, but there are problems peculiar to studying Inflammation Therapy.

Randomization requires that all subjects undergo a similar routine to standardize the study outcome. But, to be effective, Inflammation Therapy requires essential lifestyle changes. It’s highly unlikely all study subjects would agree to these changes or comply with them.

Control with blinding will be impossible because the lifestyle changes of IT require a high degree of subject cooperation, and investigators must give instructions about lifestyle changes. Herxheimer reactions might be considered an adverse event if investigators were blinded, and Herxheimer reactions need to be managed to maintain safety.

Control with a placebo isn’t possible because of the Herxheimer reaction. Investigators and Internet-savvy subjects will know who is taking a placebo when they do not experience Herxheimer reactions.

Inflammation Therapy relies on a combination of drugs working in a synergy, not on a single drug.

There are also ethical considerations in doing an RCT. Informed consent is needed in order to “do no harm”, especially in the standard treatment group since studies prove it has many adverse side effects.

One huge question is whether putting patients on a placebo would be ethical, when anecdotal reports indicate a very high level of efficacy of the treatment?

Also of interest:

Desperately Seeking Cures - How the road from promising scientific breakthrough to real-world remedy has become all but a dead end.

The Truth Wears Off