Clinical trials for prescription drugs

Last week I mentioned that I’d been closely reading Karl Denninger’s Market Ticker for the latest news.

After the Connecticut killings in December, Denninger featured several anti-gun control posts which have generated much debate amongst his readership.  He and his readers would like the debate opened up to understanding what role psychotropic drugs play in these mass murders.

Much of what is in my posts this week comes from Denninger and his readers. As we are venturing into the dark art of psychotropic drugs, it seems only fair to begin with an account of how drug trials are conducted in the United States.

Some of this information will be new, some of it won’t be. Archerymom, one of Denninger’s readers, has worked in this field for a quarter-century. She describes the process (emphases mine below):

For anyone who might be interested and doesn’t already know how the clinical trial process works – I have worked in the area of clinical trials – through project management, monitoring and report writing, for the past 24 years. And knowing how the process works – I diligently research on my own before I agree to take any “newly marketed” medication or even give my children medications.A pharmaceutical company that has a drug that has been tested through bench research and is believed to show clinical benefit can request approval through the FDA to begin human clinical trials. These human clinical trials are done in 4 phases:

Phase I: This is the first time the drug is introduced to man. It is almost without fail conducted in a very small sampling of healthy, male volunteers, usually at an Inpatient Phase I facility. Many of these facilities are located in college towns, because volunteers are paid for agreeing to participate in these trials. These trials can often require the volunteer to stay full-time at the facility for a month or more – the purpose of this Phase I trial is to try to find out all they can about the side effects, half-life and elimination profile, etc. of the drug using the dosages they assume will be effective once in the actual patient population. Sometimes the drug is compared to placebo during these trials. Blood draws are often completed on these volunteers hourly to establish how the drug is metabolized. Urinalysis is frequently done, food and drink is monitored, etc. to try to get a complete picture of how the drug “acts” in a “normal, healthy person”.

Phase II: If Phase I shows promise of relative safety, they then move on to Phase II trials. This is still conducted in only a small sampling – but in actual patients for whom the drug is intended this time. Again, the primary purpose of this trial is to get a picture of the side effect profile, how the drug is metabolized, and to determine the optimal dose ranges.

Phase III: If Phase II shows promise and is continuing to show relative safety, they move on to Phase III trials. These are usually large-scale trials, conducted across the US and sometimes internationally, to get a larger sampling of how the drug behaves in the patients who will be taking it. Large-scale usually means several hundred to a few thousand or so patients actually taking the drug. They usually know what side effects they “expect to see” and are tweaking the dose-ranges for efficacy. Many of these trials are placebo-controlled to attempt to show their particular drug is better than placebo at causing a desired outcome.

Phase IV: These are “post-marketing” trials completed once the drug is on the market to continue to collect data about how the drug is performing in patients and to perhaps compare the drug in combination with other drugs.

Once the pharmaceutical company finishes all of their Phase I-III trials, they file their final application with the FDA to get their drug “approved” for marketing. The FDA reviews all of the clinical trial data that is submitted with this application to see if the data supports the risk / benefit analysis the the company has claimed and to ensure the proposed “labeling” that will go on the drug actually conforms to what the clinical trials “prove” the drug can do and what the side effect profiles are.

This process from Phase I – III can take years – 5-10 years or more, not counting time spent on bench research, depending on the drug. As you can see, with a 20 year patent life – all this research and clinical trial time eats into the time they have once the drug goes to market to make their money back before generic equivalents can take away market share. The push to make money once the drug is on the market and recoup research costs is HUGE.

As you can also see, even though a medication is tested in “large scale clinical trials”, a few hundred to a few thousand patients is really only a drop in the bucket compared to the hundreds of thousands of patients who will probably end up actually taking the medication. This is a big reason why we see some drugs that they “thought” would have a relatively safe profile have to be re-evaluated once massive numbers of patients start taking it and side effects show up they didn’t anticipate.

Now a fact many people aren’t aware of: Many drugs, both over the counter and prescription, given to pediatric patients today have never, ever even been tested in pediatric patients. Pediatric patients are classified as those from birth to usually age 18 – age 21 for certain sub-specialties.

Think about it. How many parents do you know that would willing want to include their child in a clinical trial for a new drug not knowing what the side effect profile might be? Not many. I’m not talking about drugs for pediatric cancer patients whose parents will desperately try new drugs at the hope of saving their child. I’m talking about run of the mill antibiotics, anti-depressants, anti-inflammatory meds – the whole long list. Many drugs given to pediatric patients on a daily basis are given with a “best guess” of dosage and risk/benefit not having any pediatric clinical trial data to know if they are right or not or what side effects might show up.

Paxil’s own website says it is not intended for pediatric patients. But that doesn’t stop medications from being prescribed “off label” – this happens every day. And just last year Glaxo agreed to pay a $3 billion fine for promoting its best-selling anti-depressants for unapproved uses http://www.nytimes.com/2012/07/03/busine….

Clinical trials have their place and medications certainly have their place, but most people have no clue how this process actually works in this country and assume that if a medication is on the market, it must be safe or it wouldn’t be there. Just another example of an overwhelming number of people in the country who don’t think for themselves, don’t research anything on their own, and assume those in “authority” must be there to protect them.

As a mom, I have seen first-hand something as innocent as an over-the-counter allergy medicine cause a dramatic personality change in my girls. Being in tune with these things, I tested a couple of times to see if it was just my imagination or if they really were acting differently when that particular medication was administered – that one is now forbidden in our home.

But how many parents out there are really that in-tune with their children? Would they put the two together? All the medicating over ADHD today – how much of that is really just kids being kids? Or kids with an allergy to something else in their environment? Look into the research done by the Feingold Association http://www.feingold.org/ about the effect petroleum-based products and food colorings can have on children. About the eczema-like rashes children can get from something as simple as an allergy to foods with high salicylate content – but how many children do you personally know who have unexplained eczema who are taking routine steroids – definitely not something we’d really want our children to have to be taking all the time.

Our country has a crisis of independent thinking – and I’m not sure what it is going to take to wake them up.

She adds:

… 3) Most clinical trials are “sponsored” by the pharmaceutical company that is doing the research and planning to manufacture and sell them. Occasionally one company will do the bench research and then sell it to another company to do the clinical trials. There are large private and government institutions that run some of their own trials – St. Jude for example, here in Memphis, is always working on developing therapies and treatments for various cancers they are treating. Some of this is in conjunction with pharmaceutical companies, some isn’t.

Karl is right – they are showing statistical significance. The ongoing saying when I was working the “corporate” side of clinical trials and not the consulting side as I do now, was that the FDA was really just approving the labeling, nothing else. In other words, the label supported what the company said they found in their research.

A clinical trial plan is submitted to the FDA to give them an overview of the protocols they plan to develop in the different phases and the FDA can require or request changes to the protocols; many studies are stopped, sometimes all the way into Phase III, because the company just can’t prove enough statistically to get the drug to market and don’t want to spend any more research dollars.

The trials are only as good as the people writing the protocols for the trials, the physicians who are supposed to be enrolling qualified patients into the trials that meet all the inclusion / exclusion criteria without exceptions, and the clinical trial monitors who then go out and review all the data collected compared to the patient’s medical records to ensure the data captured and submitted for the trial is correct, the patients are real, etc. Then it is up to the data managers who capture the collected data and the statisticians to accurately interpret the data that was collected – all this then becomes the report that goes to the FDA when they seek marketing approval. It can take the FDA 10 months, sometimes more, to review all the data once the final reports are submitted before they make their decision. There are exceptions for some classes of drugs and these are “fast-tracked”.

When I worked in pharmaceuticals, one of the senior managers told me that a lorry load of final trial-related paperwork used to be sent to the FDA — multiple copies all in one go. With the advent of email and attachments, I do not know if this is still the case, however, there is much which needs to be submitted for approval.

This is by no means saying that people working in the pharmaceutical industry are inattentive or unconcerned. They are highly intelligent and very professional. I enjoyed my many years working with them.

That said, even during my time in the industry — the 1980s — every pharma firm could see the end of the gravy train was coming. Development of and research financing for new drugs was starting to run out.

It is this situation which concerns me and many other Westerners. Are the old-fashioned ethics still a part of Big Pharma?

I found it interesting to read how Archerymom actually tested allergy medicine on her daughters and dumped one product.

Perhaps it is time more parents followed her example.

This does make me think twice about the increase in asthma, allergy and aggression complaints. Maybe these are simply related to certain drugs, whether over-the-counter or prescription.