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

 In Biopharmaceuticals And Medical Devices: A General Overview I, we looked at the underlying basis of all drugs (pharmaceuticals and biologics) and discussed the development of a compound from initial discovery to the completion of Non-Clinical Laboratory Studies and the decision to move forward.  Today, we are picking up with starting clinical manufacture and clinical trials.

There are really three streams here:  clinical trials, clinical manufacture, and regulatory submission.  I am going to defer the regulatory submissions to later in the week as there are some small similarities with the Medical Device process.

Clinical Manufacture

Clinical manufacture is the manufacture of a drug to support a clinical trial.

Typically, clinical manufacture is divided into two phases, the manufacture of the actual compound (called an "Active Pharmaceutical Ingredient" for pharmaceuticals and "Drug Substance" for biologics) and the manufacture of the finished form of the product such as pills, capsules, filled liquid vials, lyophilized solutions, etc. called the  Drug Product.

The work done in the investigatory and pilot plant manufacture will be scaled up in volume to support the clinical trial, for example from a 5 L fermentation to a 50 L fermentation to a 600 L or 1000 L fermentation.  Process Development will work to find the ideal conditions for manufacture and all required buffers, medias, or reagents.  Process Sciences will develop criteria to evaluate the product - called "specifications" - which will allow testing during manufacture ("in process"), after manufacturing ("release"), or over time to evaluate how long the drug product remains "good" ("stability").  They will also identify tests to support these criteria.  

At some point, the developed process and associated tests and specifications will be transferred to the Operations Group.  Here, a variety of operations - Manufacturing, Quality Assurance, Purchasing and Supply Chain, Quality Control - will purchase and test incoming raw materials, write and approve manufacturing records for every part of the process, write and approve testing documents for all identified tests, and create final release documents so the product can be evaluated and made available for clinical trials.  The facility to be used will have to demonstrate that the meet the required regulatory and physical conditions for manufacture including temperature and humidity control, air particulate control, and micro-organism control. The equipment to be used - both manufacturing and testing - will need to be qualified to verify it is installed correctly, works correctly, and works for the process. Likewise, all quality control testing will have to be qualified to verify that the tests are repeatable, give verified data, and can be performed by multiple personnel potentially in different labs.

One note: development of the manufacturing process and manufacturing may be conducted in-house at the company or outsourced to a third party vendor, called a Contract Manufacturing Organization ("CMO") or Contract Development and Manufacturing Organization ("CDMO").  There are trade-offs between time and money; for many small companies they have no choice but to use a CMO as building out and qualifying an in-house manufacturing plant can be expensive and time consuming.

In the background of all of this (and by regulation), every company has a Quality System, which is the System put in place to guarantee that all product manufacture is conducted in such a fashion to ensure the identity, strength, purity, quality, and safety of the product.  This includes instructions on how to do things ("Standard Operating Procedures", or SOPs) for every aspect of the organization that is regulated, how to evaluate issues and failures (Deviations or Nonconformities), how to make improvements (Corrective Actions and Preventive Actions), how to manufacture and test the product (as above), and how to release the product. For all of these documents, evidence of training must exist.

Assuming all of this is in place, manufacturing will start.

Manufacturing will often start with a "non-GMP" batch, sometimes called an Engineering Batch.  This lot cannot be used for clinical trials but can demonstrate that the process can generate the Drug API/Drug Substance/Finished Product at sufficient scale and with sufficient quality.  If successful, manufacturing will move into GMP/ Clinical Trial material mode.

As trials advance (see below) the manufacturing and testing will progress as well.  As more is known about the product, tighter controls will need to be put in place.  Sometimes a problem only reveals itself over time through stability, which may mean going back to development.  Better and more extensive testing will develop.  And the process size will scale up as well to support commercial manufacture; for biological products, up to 20,000 L fermentation vessels exist for manufacturing

Clinical Trials

Clinical trials for Drugs in the U.S. (and largely, the world) are divided into three phases.  Each phase gathers information about the product and its impact on patients, but each phase also has a primary goal:

Phase 1 (also Phase I or P1) evaluates safety, or "Is the product (at a high level) safe?"

Phase 2 (also Phase II or P2) evaluates efficacy, or "Does the product do what we think it should do?"

Phase 3 (also Phase III or P3) evaluates dosing range, or "What is the best dosing level that maximizes benefit and minimizes patient impact?"

The primary concern of all Clinical Trials is ultimately the safety of the patient (this largely derives from World War II, where live in human testing was conducted (Read up on the testing in concentration camps and Unit 731 of the Imperial Japanese Army.  It is horrifying.).  To this end, 21 CFR Part include items specifically around the involvement of patients, physicians, and companies (Parts 50, 54, 56, and 312) as well as the International Committee on Harmonization document E6.  In short, patients must be fully informed and able to withdraw at any time.  Physicians cannot have a significant financial interest in a company for which they are testing a Drug Product.  An Independent Review Board ("IRB") must review all documents associated with a trial and make sure it protects patients, is ethical, and is scientifically justified.

To use an unapproved Drug Product ("investigational drug" in the regulated world) in humans, the company ("Sponsor")  is governed by 21 CFR Part 21 Part 312, Investigational New Drug Application.  In short, one has to provide an Investigational New Drug Application (called an "IND") and have it approved by the US FDA prior to starting the trial.

The IND will provide a description of the product, a history of its development, proposed release and stability criteria,  a summary of the Non-Clinical Laboratory Studies (GLP and non-GLP Compliant), and the proposed Clinical documentation.

Leading up to the IND, the company is developing documentation for the Clinical Trial:  an Investigator's Brochure, to explain the product and the trial to physicians and site staff; a Pharmacy Manual to explain how to prepare the product for patient use; an Informed Consent which explains to the patients about the trial and their potential participation and potential risks; a Clinical Protocol, which explains how the trial is to be conducted, what is to be tested, how patients should be included or excluded based on criteria, and the endpoints of the trial; the Statistical Analysis Plan created, which ensures that the study has the minimum of number of patients to power the study statistically and can deliver definitive data; and the Clinical Trial Documentation, which is used to record all data for the trial (often this is now electronic).  All of the documents are reviewed and approved internally by the company, by the IRB and by the FDA upon submission of the IND.  Any of these parties can require changes to any of these documents, which then need re-approval.

At the same time, the company is also identifying sites which would be willing to conduct the clinical trial. This is a lot more work that it may sound like:  there are always more trials than sites and some sites are more desirable than others.  For each site a contract must be written and signed, a budget prepared and approved (sites are paid to conduct these trials), all the documentation above provided, and supporting supplies provided.

Conduct of the Clinical Trial

Assuming all the product is manufactured and approved, all clinical documentation is approved, clinical sites have been identified and initiated, and the IND has been approved (or revised and approved as needed), the clinical trial can start.

Clinical trials escalate in size and scope as they progress.  A Phase 1 trial can have as few as 20 patients and 3 sites; a Phase 3 trial can have as many as 7,000 patients and multiple sites in multiple countries.  Study progress is based on the ability to enroll subjects - and have them complete the program.  Not all patients can be evaluated.  Patients may be rare, depending on the inclusion criteria.  If an Unexpected Adverse Event or Serious Adverse Event happens - something that causes transient, partial, or permanent damage to the patient including death or disablement - the trial may be stopped temporarily or permanently. 

During the trial, company personnel from the Clinical, Medical Affairs, Regulatory Affairs, and Quality Assurance departments work intensely with the sites.  Clinical Trial Monitors or Clinical Trial Associates contact and/or visit sites frequently to check up on the trial and audit documentation and product.  Medical Affairs personnel assess data and answer questions.  Quality Assurance evaluates potential complaints.  Regulatory Affairs reports any Unexpected or Serious Adverse events to the Regulatory Authorities.  Meanwhile as needed, Manufacturing, Purchasing and Supply Chain, Quality Assurance, Facilities, and Quality Control continue to do their jobs to ensure that Drug is available for the study.

Periodically the trial may be evaluated by statisticians to evaluate the data.  There may be a reason to cut the trial short, either because the data is overwhelmingly indicative of the endpoints or the data demonstrates no progress to the endpoints or is even risky.

Thoughts

As you can hopefully see, there is a lot to "testing the product in a person".

Perhaps unsurprisingly, a main factor is cost - not just of the all the work to make the product and get to the clinical trial, but for the clinical trial itself.  I would hesitate to provide a number for even the most basic of clinical trials, but it is easily in the millions of dollars for a Phase 1 trial - and goes up from there.  

And the cost escalates of course.  Phase 2 trials are more expensive than Phase 1 trials, and Phase 3 trials are even more expensive.  And the cost of scaling up manufacturing and testing increases as well.  

The funding of a company really determines its future at these stage. Most companies have enough funding to complete a Phase 1 clinical trial.  The hope is that the data from that Phase 1 trial will support getting additional funding to continue to Phase 2, then Phase 3.  Obviously, a failed Phase 1 trial pretty much can spell doom for an early stage company and many layoffs occur after a "setback" in the Phase 1 trial.

But it can happen at any step.  Phase 2 trials fail as well, and Phase 3 also.  The cost of those failures is significantly increased in terms of money as well as prestige:  a Phase 3 trial means that at some point, some signal was missed in an earlier trial.  This can reflect poorly on the company's executive management and scientific basis.  Established companies with commercial products can survive this; most non-commercial companies cannot.

And we have still not arrived at the ability to sell a single Drug Product and thus generate any revenue for all of the work done to date.

Tomorrow we will turn our attention to Medical Devices and how they reach this same point of pre-submission.