June 25, 2017

Meet Worcester’s clinical trial pioneers

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Art Simas / For Worcester Sun

Dr. Charles Birbara and Mary Coughlin

Clinical pharmacology. Clinical trials. These phrases may not roll off the tongue with ease. And they probably do not convey a warm and fuzzy feeling … think of cold, hard surfaces, procedures, and questions, questions, questions.

Let’s debunk these perceptions right now. Everyone here wants you to get better. And they do not stop looking for answers to your situation.

From its beginning as Clinical Pharmacology Group in 1989 inside the former City Hospital on Queen Street, to its present quarters at 25 Oak Ave., Advanced Clinical Care has been headed by Director Mary Coughlin, R.N., and medical director Dr. Charles A. Birbara.

Coughlin has been involved in more than 500 clinical trials. She and Dr. Birbara have been at the forefront of transforming painful, debilitating diseases into pain-free or almost pain-free lives for their patients.

“My initial role (in the business) was to replace a coordinator who had left,” Coughlin said. “At that time (1975), there was only one study for osteoarthritis with about six patients enrolled. It was really just a part-time job.

“In the beginning, in my spare time, I would call the various drug companies, asking for the rheumatology departments, and try to talk to someone about what trials were going on. We got involved in some trials that way,” she said. “Then, if we did well with enrollment and with the data collection, we would get several more trials with that company.”

In the 1980s and early 1990s, drug companies wanted to control their own trials with their own personnel. But as time went on, the companies drifted from this insular approach.

“Soon there were more CROs (clinical research organizations) that were hired by the drug companies to run the studies. The CROs would find the trial sites and do all the training and monitoring for the pharmaceutical company,” Coughlin said. “A large CRO would have hundreds of studies in all different fields of medicine. If we did well in a study, the CRO might have a trial for another indication (symptom), and ask us to participate.”

Far from their lean, uncertain early days, Coughlin and Dr. Birbara have been among the vanguard in their field, developing a specialty in rheumatology and helping to bring pain-relieving drugs like Humira and Xeljanz to sufferers of arthritis, Crohn’s disease and other disorders.

“We’ve made enormous strides,” Dr. Birbara said. “When I started practicing medicine (in the 1960s), the only thing that we could offer for treatment was aspirin. But we treated with huge doses of aspirin … to the point of toxicity and gastric ulcers and bleeding.

“So how do we modify these treatments to make them less toxic and harmful?

“If we can relieve pain differently, and get people away from opioids by understanding how other pain pathways can be impeded, that would make a huge difference in people’s lives.”

The rate at which new drugs are coming on the market has markedly increased for a number of reasons, according to Dr. Birbara, including the nearly unfathomable financial stakes held by large pharmaceutical companies and equally incredible scientific advancements.

Researchers, for instance, are now developing methods to carry a toxic molecule into a specific cell, opening the door to potentially killing malignant cells while leaving surrounding cells intact.

“Right now, you need the clinical trial in order to bring any of these medications to market, and the complexities of doing a clinical trial, given the medical legal situation we now live with, are very extensive,” Dr. Birbara said.

He added, “Throughout all of this, our main focus is the safety of a patient involved in a trial – and making sure they get an adequate evaluation, which is much greater than what they would receive in a typical office visit. Sometimes we can do things within a context of a clinical trial that we could not do within the parameters of a patient’s private insurance.

“We’ve played a tremendous role in giving care to people who have no insurance … or else they would never be able to pay for this opportunity.”

Initially, and still now for the most part, the patients find out about clinical trials through private practice referrals, including Dr. Birbara’s practice, recruitment advertisements in magazines and through the Internet and word of mouth, Coughlin said.

Dr. Birbara is an expert in the field of autoimmune diseases. He has had a practice in Worcester for more than six decades, and is an associate professor of medicine at University of Massachusetts Medical School. He graduated from Harvard University with a B.A. in Biology and received his M.D. from McGill University in Montreal.

Coughlin is a graduate of Regis College with a B.A. in Psychology; Anna Maria College with a M.A. in Psychology; and Worcester State University with a B.S. in Nursing. She serves on the nursing advisory boards for Abbott, Bristol-Myers Squibb, and other companies, and travels to teach nurses how to administer new biologic medications.

There are four phases to a clinical trial. Usually, a clinical pharmacology trial will begin during Phase 2 (2A and 2B) of a particular drug’s journey toward Food and Drug Administration (FDA) approval.

“Phase 2A is very controlled, with smaller groups,” Coughlin explained. “We’re looking for the appropriate dosage in milligrams, and we note the timing of the drug. … Unfortunately, many people are excluded because we’re focused solely on safety in dosing.”

However, phase 2B is different. The highest dose is eliminated and adjusted to help predict efficacy and a more remote possibility of toxicity in the patient

“With every patient, we take a very detailed compilation of all types of historical symptoms [e.g., rash, muscle weakness],” Dr. Birbara said, “and determine if this is a recurring issue or a new problem.”

Then they move on to Phase 3, which is the typical clinical trial.

What Can You Expect from Participating in a Clinical Trial?

Participants will be asked to thoroughly read information about the drugs that may be administered, possible side effects and procedures that will take place during the length of the trial. Often one will be asked to give blood and/or urine samples, and will be asked questions about the person’s condition since the last time they were in the office.

Sometimes patients will be given a stipend to pay for their expenses for gas and parking.

But the most important thing about a clinical trial is that there is no charge to patients, and you may increase your overall health and quality of life.

Biologics and Genetic Engineering

“The development of biologics in the late 1990s and early 2000s was huge for us,” Coughlin said. “We had patients with rheumatoid arthritis who had [a] severe disease and there were few options to treat them. We started working with Humira, and found this drug totally changed their lives. These patients were able to start living fully again, enjoying life, going back to work, all without constant pain and disability that they had endured for years.”

“Throughout all of this, our main focus is the safety of a patient involved in a trial – and making sure they get an adequate evaluation, which is much greater than what they would receive in a typical office visit. Sometimes we can do things within a context of a clinical trial that we could not do within the parameters of a patient’s private insurance.” — Dr. Charles Birbara

Some of these early Humira studies lasted 10 years; and during this time all patients got their medications and care for free.

Dr. Birbara explained, “Humira belongs to a class of drugs called biologics. Biologics are normally derived from a living organism, such as humans, animals, microorganisms or yeast. The therapy is based on proteins, usually antibodies. The proteins are developed using DNA technology, otherwise known as genetic engineering.”

In the January 2017 newsletter, MedicalNewsToday, ‘’Humira is a drug that is used to relieve pain and reduce inflammation in people with a number of autoimmune diseases … rheumatoid arthritis, chronic plaque psoriasisCrohn’s diseaseankylosing spondylitis, psoriatic arthritis, and polyarticular juvenile idiopathic arthritis.”

[Editor’s note: There have been reports of the unintended side effects of Humira, such as weakening the immune systems of users and leaving them vulnerable to dangerous ailments. This $2.4M jury judgment is one example.]

Dr. Birbara said that over the years, “There is no doubt—we (here in Worcester) were the leaders in the national clinical trials for Humira, as well as Orencia, Stelara, Xeljanz and Talz.”

Battle of the Arrogant Molecules

The evolution of clinical pharmacology began with studies of non-steroidal inflammatory drugs, according to Dr. Birbara. “We were looking at naproxin, meloxican and various other NSAIDS (nonsteroidal anti-inflammatory drugs) because we did not have this tremendous knowledge of molecular medicine that we have today. So the medicine eventually became ‘targeted.’

“In the 1990s, there was recognition that there were certain molecules – or cytokines – that allow cells to talk to each other. And we also saw that certain cytokines were very important to the development of a disease. And if you blocked that molecule, a disease process could not develop or progress.

“So TNF (tumor necrosis factor) was developed. TNF was a key molecule that was tied to the inflammatory process,” he added.

“Later, we also began to recognize the role of cells in the disease process. So before the pathology could develop, one needed to have certain cells – T cells – for particular diseases. T cells were known to be very important in rheumatoid arthritis (RA). So Bristol Myers Squibb developed a drug called Orencia, which impeded the flow activation of a T cell to participate in the inflammatory response,” he said.

“So one needed that molecule to create a cell which was pathologic, and which would participate in creating a disease state.”

In Europe, two authors, Marco Cavaco and Joao Goncalves of Lisbon, Portugal, wrote about the same process in their research manuscript titled, “Interactions between therapeutic proteins and small molecules: The shared role of perpetrators and victims.”

Now the drug companies realized that pharmacology could block molecules and cells. So they began to take a look at other molecules that participated in the inflammatory response, and developed various cytokine molecules and cells that participated in the disease state.

After a while, Dr. Birbara said, the drug companies started to make smaller molecules … which could use a non-protein dose that could be given orally instead of by injection. “And they developed a small molecule for rheumatology for intracellular pathways, as opposed to the large molecules which were exo-cellular.”

This change certainly was a hit with patients because they prefer to take pills instead of getting injections, Coughlin said.

Phase 4

In Phase 4, the drug is approved by the FDA — or not — but the trials and testing don’t end there.

Advanced Clinical Care (and others) have conducted studies and clinical trials with drugs that are already in Phase 4 – to search for possible “indications” where one drug may benefit another population that may suffer from a different illness.

Coughlin explained, “If a drug manufacturer can prove a biosimilar Humira, such as Talz, is equivalent to Humira, then when that biosimilar gets approved, it’s approved for all the indications of the original Humira.”

Dr. Birbara said the same thing can be applied to the drug Remicade, which is FDA-approved for rheumatoid arthritis, psoriatic arthritis, psoriasis, Crohn’s disease, and ankylosing spondylitis.

He emphasized that biosimilars are not generic drugs. “A generic drug is the identical copy of a particular molecule. With a biologic agent, you’re dealing with a huge complex of amino acids, which have a particular structure … and in that structure there may be various pockets.

“So the effectiveness of a particular drug depends on a ‘lock and key’ situation,” wherein the molecule is looking to provide a similar effectiveness,” he said.

“We are searching for better results for existing patients who, for whatever reason, do not have the anticipated results that we hoped for with treatment,” Dr. Birbara said. “So we’re moving quickly from many directions. And soon, we’re going to be doing a trial with a combination of two biologics, which hasn’t been done before.

“And we’re going to do another one for rheumatoid arthritis where there is a molecule on the surface of a particular cell – and that cell is a key player in doing joint destruction. But that cell also happens to have, on its surface, a particular molecule that is an antibody compound that is beneficial for the patient.”

He said he and the team are looking at options for patients who have not achieved their optimum level in the resolution of the disease. “We think it could be exciting and significant, especially for someone who is not doing well and needs more,” he said. “What we’d be doing is blocking two molecules, which play a role in disease progression.”

Coughlin summed up her work in clinical pharmacology by saying: “Every day you hear something new. Every new trial that is proposed to us is totally different from what we thought it was. It changes our beliefs in treating the disease.”

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