Biopharmaceuticals And Medical Devices: A General Overview I (Drugs)

FOTB (Friend Of This Blog) Leigh from Five Acres and A Dream made the following comment in my update on Week 4 of Hammerfall 3.0:

"Being in the "retired category of folks myself, I feel really out of the loop in understanding such things, but I have to ask why your particular industry seems to be struggling so.  I mean (probably naively), it's in the medical/health care arena, and people always need these things, so it would seem that the demand for the supply should keep the industry thriving.  I'm guessing the answer is extremely complicated but it's one of those things that just doesn't make sense."

It is a fair question - after all, the Pharmaceutical/Biotechnology/Medical Device Industry impacts almost everyone at some point (if you have used an aspirin or a bandage, you have participated).  Hopefully I can shed some illumination.  

For reference how I know about this: I have over 25 years of experience in the industry in Manufacturing, Quality, and Project Management had have worked for almost every type of manufacturer (pharmaceutical, biologic, medical device) for products being developed, products in the approval process, and approved products.

I will start with Biopharmaceuticals and then move to Medical Devices.

(Note 1:  This is a very generalized description of the process.  There is a lot of underlying details and processes which, while important, would rapidly spiral of control.)

(Note 2:  For the purposes of this discussion,  I will just use "Drugs" to describe both pharmaceuticals and biologics.)

The most important thing to remember about all of this is that all Drugs in the U.S., be they small molecule (e.g., generated by chemical or "pharmaceutical") or large molecule (generated by biologic process,  or "biologics") are regulated by U.S. Law.  The history of how we got here is long, but suffice it to say in our day, the US Food and Drug Administration (FDA) is responsible for ensuring that all drugs are safe and effective.  The origins of this authority are found in the 1938 Food, Drug, and Cosmetic Act (FD&C Act) and have been expanded ever since.  The regulations for drug manufacture (and much of biologic manufacture) is found in the Code of Federal Regulations (CFR), Title 21, Parts 210 and 211 (and part 600 for certain biologics).  

Unlike International Standards like the International Standards Organization (ISO) or the International Committee on Harmonization (ICH), these regulations must be complied with (as opposed to the standards, which must be conformed to) - unless the standards have been taken into U.S. law as a consensus standard (which many have been).  Every nation has their own set of regulations that must be complied with:  for example, if you are going to sell products in the U.S. and Europe, you have two sets of regulations to comply with.  Often these are similar, but sometimes there are differences which can be significant and must be planned for.

Thus everything that has to do with drug development and drug manufacture is regulated.  The closer one gets to submission for approval, the more regulated things become.

The second most important thing to remember is that all Drugs have side effects.  Every single one.  Drugs are thus evaluated on a risk/benefit basis: does the benefit of a drug outweigh the risks and impacts?  Everyone is familiar with the impact of chemotherapy on the individual in terms of visible impacts (loss of fast growing cells like hair follicles) and not quite as visible impacts (loss of appetite, nausea, loss of ability to taste, lowered immune resistance).  In this case, the benefit (fighting cancer) outweighs the impacts and risk (all the physical impacts above and, frankly, dying of an infection due to a lowered immune system).

Drugs all start in a lab.  There is a promising compound or a significant unmet need that drives scientists to look for a solution.  After going through hundreds or even thousands of compounds (via lab screening or computer models), they discover one which (maybe) has an effect on a condition on a medical condition.  Most likely it is perceived as a novel impact, as "me-too" drugs have a higher bar to succeed in the market.  Also, multiple labs may be working on the same condition, so the development becomes a race to be first (for a novel compound) or a race to be more effective (where a drug already exists for a condition).

Once a compound is identified, it has to be tested to verify that it has the effect that scientists think it has.  This is done in several ways - in silico ("in silicon", or using computer models). in vitro (literally "in glass", or under controlled laboratory conditions with the target cells or molecules), in vivo ("in the living" or using live animals (only, at this point - live humans come later),  Generally the progression is from in silico (where available) to in vitro (cell studies) to in vivo (animal testing).  At the same time as the product is being tested, a basic manufacturing process is being designed:  what conditions, what medias and buffers, what manufacturing steps have to be in place to make "the compound".  Not only does the compound need to have an effect, it needs to be able to be manufactured.

Assuming we now have the compound, it has to be put through some level of paces to make sure it is worth moving forward with.  Typically the product will be characterized (to learn all they can about it) and placed against a set of criteria that will define if the product meets the anticipated needs of the criteria identified (sometimes called "Target Product Profile") and can be manufactured.  If it meets both criteria, it will move forward (if not, of course, it gets discontinued).   At the point (or slightly before), small scale lots (pilot lots) will be manufactured and animal testing starts.

No-one I know of in the industry is fond of animal testing (also called "Non-Clinical Laboratory" Testing), but the other option at this stage is "testing straight in people", which for some pretty strong historical reasons is a bad idea.  A species which simulates the human system or condition to be tested is selected (typically starting with mice and ending with non-human primates, but other species animals may be used based on the nature of the disease or condition being evaluated) and the product tested per a protocol.  Often, necropsy is performed and the data reviewed, looking for 1) Efficacy and 2) Impact to to the physical systems.  Pharmacokinetics (the movement of the drug through the body) and Pharmacodynamics (the biological, physiological, and molecular impact of the drug on the body) are measured.  For this testing, the controlling regulation is 21 CFR Part 58, Good Laboratory Practice for Non-Clinical Studies (also referred to as GLP).  These test can be either non-GLP (for general data generation or proof of concept) or GLP (required to move the product into clinical trials).

All of this does not come cheaply, of course.  Scientists require labs, and labs required equipment and reagents and personnel to run them.  Small manufacturing lots need a pilot plant internal to the company or an external contract manufacturing organization (CMO) to manufacture them.  And Non-Clinical laboratory studies need to be conducted:  as of last year, a small mouse study ran $250,000 at a minimum and a non-human primate study $1.3 million.  Generally there is more than one mouse study and a minimum of one major animal study (such as non-human primates).   Add to that that scheduling for these studies is anywhere from 4 months (for mice) to 9 months or more (for non-human primates).

If helpful for reference, products that I have worked on to get to this point - not including internal overhead for personnel, lab space, equipment, etc. - have cost between $2 million and $4 million.  Just to get to the point of possibly using it in an early clinical trial.

Assuming all of this data indicates 1) There is some benefit; and 2) The benefit outweighs the impact, and 3)  The compound can probably be manufactured,  the compound will likely be moved to scaled manufacture and clinical trials of the compounds in humans (which we will review tomorrow).