Investigational New Drug Application

An Investigational New Drug Application (IND) is a request for authorization from the U.S. Food and Drug Administration (FDA) to administer an investigational drug or biological product in humans.

This IND submission step is the precipice between preclinical drug development and clinical trials. Preclinical development for most drugs averages out to be five years. That means that the company has sunk years of work and millions in funding in trying to find a drug the treats a certain indication, has tested that drug in an animal model, and is now ready to sink five more years and millions more to test it in humans.

After this point, the drug has a 10-20% chance of making it to the market. These risks, great even at the first regulatory step imposed by the FDA, are what make pharmaceuticals so expensive. In braving those risks, companies find novel therapeutics for diseases with no cure and in turn reap high profit margins.

A Pharmaceutical company submitting an IND must include:

Pre-clinical data

This includes the effect (pharmacology) and adverse effect (toxicology) of the drug on an animal model. The questions scientists want to answer here are, can the drug be validated? Does the drug treat the disease indication the company wants it to? How safe is the drug? How much of the drug can you put in the animal before the animal dies? Why should the FDA believe that the animal model is comparable to humans? Scientists must include all of these answers before the FDA will allow them to inject the drug into healthy human beings in the clinic.

Proposed Phase I protocol

The preclinical data provides the rationale for a protocol for injecting the drug into healthy humans. Phase I studies are safety studies, designed to see what dosage of the drug should be administered and how that dosage is absorbed, trafficked, metabolized and excreted in the body. Persistence of the drug in the body will also be measured. Details like where the trials will take place, how patients will be selected, and what kind of therapeutic endpoints scientists want to reach are all included in the protocol. The purpose of this protocol is to ensure the safety of clinical trials, determine parameters for human studies and provide a scientific rationale for the protocol. Frequently, this rationale comes from good preclinical data.

A well developed and controlled manufacturing scheme

This includes the definition of the drug product, a plan for manufacturing it and a plan for scaling up production of the drug in order to meet full current Good Manufacturing Practices (cGMP) compliance by the end of clinical trials. This task is a complex composite of various challenges. Drug products must be sterile, potent and pure, and consistent. Quality Controls must also be in place to ensure these things. And unlike the manufacture of chemicals, biologics are difficult to make consistently pure. Further, scaling up manufacturing to make more product as later clinical trials grow in size is a daunting task. Frequently, increasing output even tenfold may require an entirely different strategy. Making biologics isn’t like cranking out more widgets by buying more machines or making them work faster. Biologics requires careful consideration of what kind of automation at what steps in the procedure should be used.

Again, at this point in development, the drug has a 10-20% chance of making it to the market. Slim odds for a drug that’s already cost millions and will cost millions more before it fails. If the company has good preclinical data, though, (i.e. the drug cures the disease in mice or dogs without killing the animal) then the small biotech company has an opportunity to look for a strategic partnership with a big pharmaceutical company to help them through clinical trials before submitting the IND. The small biotech company gets money and clinical expertise from the pharmaceutical company and the pharmaceutical company gets license to use the small biotech company’s innovation. If the company decides not to partner and enters clinical trials alone, the company won’t have the opportunity to partner again until they have good results in the clinic, which is a crap shoot at best. And for a small biotech company living hand to mouth, the entire fate of the company lies on that risky bet.

For an example of this decision making process, see also:
Avigen: using gene therapy to cure hemophilia