From Drug Discovery to the FDA Approval Decision
Summary by Derek DiRocco, PhD.
Filing the IND
Before testing in humans can begin, the sponsor (pharma company) must submit an Investigational New Drug (IND) application to the FDA. This filing is a report of all relevant pre-clinical data gathered from experiments conducted with the candidate compound. All animal pharmacology and toxicology data is reviewed in order to determine if the drug will be safe (potentially) to human subjects. The chemical composition and features of the drug are also included in the IND, as well as information on the manufacturing procedures required to produce the drug. This is to ensure the drug can be made consistently, without variation, and in large enough batches as needed. Additionally, extremely detailed information regarding the structure of the planned clinical trials must be provided. The IND must show the safety of patients has been accounted for and that the doctors or groups running the trials are competent to perform duties associated with running a safe trial. All clinical trials will also be reviewed by the Institutional Review Board (IRB) where the trials will take place, which will ensure procedures to obtain informed consent of all clinical trial participants is in place. Importantly, clinical trials are monitored continuously by statisticians and can be stopped by the FDA or the sponsor institution at any time. Conversely, if a drug is suspected of doing well all participants, including those receiving placebo or other treatment can receive drug as it would be unethical to withhold the drug from a patient in need.
Phase I Clinical Trial
Once the IND application and the IRB has approved clinical trial protocols human testing can begin, typically in phase I clinical trials (although phase 0 trials are also conducted http://en.wikipedia.org/wiki/Phases_of_clinical_research). In phase I trials 20-100 patients (estimated cost $22,000 per patient) are enrolled to primarily test the safety of the drug being tested. Occasionally, patients with the disease being treated are enrolled. This usually happens when the treatment is being tested for a terminal disease such as cancer or HIV and the treatment would be expected to have side effects in healthy individuals. In addition to the safety of the drug (pharmacovigilance) the pharmacokinetics (what the body does to the drug or ADME/tox) and pharmacodynamics (what the drug does to the body or cellular effects, drug binding and distribution, phenotypic effects). In order to determine toxicity and safety trials may be run as Single Ascending Dose or SAD. In SAD trials one dose is given to a group of patients and if there are no undesirable effects another group will received an increased dose. If side effects begin showing up at a particular dose that is considered the Maximum Tolerated Dose (MTD). In Multiple Ascending Dose or MAD trials multiple doses are given and pharmacokinetic and pharmacodynamic studies are done to determine how repeated dosing is tolerated. Finally Food Effect studies are done where groups are given drug with food and with out food to determine if this can effect PK/PD of the drugs. So, overall Phase I studies determine a safe dose range of the drug in order to move on in the drug development process.
Phase II Clinical Trial
Phase II trials are much larger than Phase I trials as they involve 100-500 patients (estimated cost $36,000 per patient) with the condition the drug is hypothesized to treat. Safety is continuously monitored and any adverse side effects are noted. Optimal dosing and dose scheduling are also being analyzed. In this sense Phase II trials act as continuation of Phase I trials and sometimes these trials are combined as Phase I/II trials. Additionally, in phase II trials researchers will also note if the drug is working as expected and if it is efficacious. Of course, researchers will always be looking for signs that the drug is actually improving the condition they want to treat. Sometimes phase II trials are designed as randomized clinical trials where patients will be randomly assigned the experimental therapeutic or a placebo/standard of care treatment. Efficacy and potency are noted and if there is promise the trial will move to a much larger Phase III trial where statistical significance of desired outcomes may be reached. If the phase II trials examining efficacy do not show any promise (or sometimes make the disease worse) the trials are halted and the drug may be deemed a failure at this point.
Filing the IND
Before testing in humans can begin, the sponsor (pharma company) must submit an Investigational New Drug (IND) application to the FDA. This filing is a report of all relevant pre-clinical data gathered from experiments conducted with the candidate compound. All animal pharmacology and toxicology data is reviewed in order to determine if the drug will be safe (potentially) to human subjects. The chemical composition and features of the drug are also included in the IND, as well as information on the manufacturing procedures required to produce the drug. This is to ensure the drug can be made consistently, without variation, and in large enough batches as needed. Additionally, extremely detailed information regarding the structure of the planned clinical trials must be provided. The IND must show the safety of patients has been accounted for and that the doctors or groups running the trials are competent to perform duties associated with running a safe trial. All clinical trials will also be reviewed by the Institutional Review Board (IRB) where the trials will take place, which will ensure procedures to obtain informed consent of all clinical trial participants is in place. Importantly, clinical trials are monitored continuously by statisticians and can be stopped by the FDA or the sponsor institution at any time. Conversely, if a drug is suspected of doing well all participants, including those receiving placebo or other treatment can receive drug as it would be unethical to withhold the drug from a patient in need.
Phase I Clinical Trial
Once the IND application and the IRB has approved clinical trial protocols human testing can begin, typically in phase I clinical trials (although phase 0 trials are also conducted http://en.wikipedia.org/wiki/Phases_of_clinical_research). In phase I trials 20-100 patients (estimated cost $22,000 per patient) are enrolled to primarily test the safety of the drug being tested. Occasionally, patients with the disease being treated are enrolled. This usually happens when the treatment is being tested for a terminal disease such as cancer or HIV and the treatment would be expected to have side effects in healthy individuals. In addition to the safety of the drug (pharmacovigilance) the pharmacokinetics (what the body does to the drug or ADME/tox) and pharmacodynamics (what the drug does to the body or cellular effects, drug binding and distribution, phenotypic effects). In order to determine toxicity and safety trials may be run as Single Ascending Dose or SAD. In SAD trials one dose is given to a group of patients and if there are no undesirable effects another group will received an increased dose. If side effects begin showing up at a particular dose that is considered the Maximum Tolerated Dose (MTD). In Multiple Ascending Dose or MAD trials multiple doses are given and pharmacokinetic and pharmacodynamic studies are done to determine how repeated dosing is tolerated. Finally Food Effect studies are done where groups are given drug with food and with out food to determine if this can effect PK/PD of the drugs. So, overall Phase I studies determine a safe dose range of the drug in order to move on in the drug development process.
Phase II Clinical Trial
Phase II trials are much larger than Phase I trials as they involve 100-500 patients (estimated cost $36,000 per patient) with the condition the drug is hypothesized to treat. Safety is continuously monitored and any adverse side effects are noted. Optimal dosing and dose scheduling are also being analyzed. In this sense Phase II trials act as continuation of Phase I trials and sometimes these trials are combined as Phase I/II trials. Additionally, in phase II trials researchers will also note if the drug is working as expected and if it is efficacious. Of course, researchers will always be looking for signs that the drug is actually improving the condition they want to treat. Sometimes phase II trials are designed as randomized clinical trials where patients will be randomly assigned the experimental therapeutic or a placebo/standard of care treatment. Efficacy and potency are noted and if there is promise the trial will move to a much larger Phase III trial where statistical significance of desired outcomes may be reached. If the phase II trials examining efficacy do not show any promise (or sometimes make the disease worse) the trials are halted and the drug may be deemed a failure at this point.
Phase III Clinical Trial
Phase III trials involve hundreds to thousands of patients (estimated cost $47,000 per patient), potentially at different study centers across the world. Basically, the experimental drug is compared against placebo, and more likely the standard of care. The test groups are randomized by a computer in order to determine which patients get the experimental drug or control treatment in an unbiased manner. Sponsor companies may run multiple phase III trials with different dose schedules, combination therapy, dose amount, and disease type. Large patient populations are used so adequate statistical inference can be made to determine safety and efficacy of the drug. Careful design of and choice of study type is essential, as these studies will give the most information to the FDA about whether or not to approve a drug and also cost the most amount of money to run.
Clinical trials currently being administered can be looked up on Clinicaltrials.gov.
If you are interested in a molecule currently being developed and want to look at which clinical trials are taking place, a search for the compound on clinicaltrials.gov will provide information about the trials currently being conducted. For example a Pharmasset compound being developed to treat hepatitis C, PSI-7977 (a nucleotide analogue and inhibitor of the viral NS5B RNA dependent RNA polymerase, can be searched in clinicaltrials.gov and a number of phase III trials are currently being run. Pharmasset, $VRUS, was recently taken over by Gilead, $GILD, for ~$11 billion dollars and the drug is also labeled as GS-7977, looking up this will also show phase III clinical trials currently being run by Gilead. Clinicaltrials.gov details a number of active, currently recruiting etc… phase II and phase III trials for PSI/GS 7977.
Submission of NDA New Drug Application
Following completion of all phases of clinical trials (I-III and occasionally phase 0, IIa, and IIb) the sponsor company will review all safety and efficacy data and if the data is satisfactory it will submit the NDA. The NDA is a compilation of all data ranging from the preclinical phase to clinical phase and also includes, final dosing and indications, chemical formulation information, and drug manufacturing procedures. The expenses of drug development aren't done - the company must pay the FDA about $2 million to file the NDA, and that does not count the huge number of man hours of employees, contractors, and consultants it takes to assemble the documents (which literally fill a truck if not submitted electronically). Once the NDA is submitted to the FDA the company will receive a prescription drug user fee act (PDUFA) date. This is the formal date on which the FDA will make its decision on the drugs approval. Typically, the PDUFA data is 10 months from submission of the NDA, however a drug may be chosen for priority review, in which the FDA will make its decision 6 months after the NDA.
Phase III trials involve hundreds to thousands of patients (estimated cost $47,000 per patient), potentially at different study centers across the world. Basically, the experimental drug is compared against placebo, and more likely the standard of care. The test groups are randomized by a computer in order to determine which patients get the experimental drug or control treatment in an unbiased manner. Sponsor companies may run multiple phase III trials with different dose schedules, combination therapy, dose amount, and disease type. Large patient populations are used so adequate statistical inference can be made to determine safety and efficacy of the drug. Careful design of and choice of study type is essential, as these studies will give the most information to the FDA about whether or not to approve a drug and also cost the most amount of money to run.
Clinical trials currently being administered can be looked up on Clinicaltrials.gov.
If you are interested in a molecule currently being developed and want to look at which clinical trials are taking place, a search for the compound on clinicaltrials.gov will provide information about the trials currently being conducted. For example a Pharmasset compound being developed to treat hepatitis C, PSI-7977 (a nucleotide analogue and inhibitor of the viral NS5B RNA dependent RNA polymerase, can be searched in clinicaltrials.gov and a number of phase III trials are currently being run. Pharmasset, $VRUS, was recently taken over by Gilead, $GILD, for ~$11 billion dollars and the drug is also labeled as GS-7977, looking up this will also show phase III clinical trials currently being run by Gilead. Clinicaltrials.gov details a number of active, currently recruiting etc… phase II and phase III trials for PSI/GS 7977.
Submission of NDA New Drug Application
Following completion of all phases of clinical trials (I-III and occasionally phase 0, IIa, and IIb) the sponsor company will review all safety and efficacy data and if the data is satisfactory it will submit the NDA. The NDA is a compilation of all data ranging from the preclinical phase to clinical phase and also includes, final dosing and indications, chemical formulation information, and drug manufacturing procedures. The expenses of drug development aren't done - the company must pay the FDA about $2 million to file the NDA, and that does not count the huge number of man hours of employees, contractors, and consultants it takes to assemble the documents (which literally fill a truck if not submitted electronically). Once the NDA is submitted to the FDA the company will receive a prescription drug user fee act (PDUFA) date. This is the formal date on which the FDA will make its decision on the drugs approval. Typically, the PDUFA data is 10 months from submission of the NDA, however a drug may be chosen for priority review, in which the FDA will make its decision 6 months after the NDA.
