The Office of Generic Drugs at the U.S. Food and Drug Administration (FDA), of course.
In 2014, generic drugs saved the U.S health care system $254 billion dollars, and with the recent outrageous price hiking of an HIV medication (cough, cough, by a greedy you-know-who), it’s even more crucial that patients are provided with the option and access to safe and effective, yet economically feasible alternatives to innovator drugs.
So, what actually happens when a drug patent expires and companies can submit their own versions of the drug to the FDA? It’s a complicated process involving many divisions within the FDA such as clinical, medical, chemistry, science, bioequivalence, and many more.
Since I work in the division of bioequivalence, I will talk about my role in the generic drug approval process. I am a primary reviewer, which means that it is my responsibility to wade through thousands of pages of documents submitted by the drug company. The work flow is as follows:
1. The Project Manager assigns the drug review to a primary reviewer. They will also assign a secondary reviewer, sometimes even a tertiary reviewer, to the same review as a part of quality control management.
2. Once I receive a notice of a new assignment, I locate the files the company submitted and start to read through the relevant documents. I will read the drug product information, pharmacokinetic and pharmacodynamics information between the test (the generic drug product and the referenced innovator/patented drug) drug products, pre-study bioanalytical procedure, to see if the method and criteria used are adequate.
3. I will also check the documents for completeness. For example, if the company forgot to include all raw data or the SOP required, then I would request an ECD (Easily Correctable Deficiency) letter to the company, then the company has 10 business days to respond to the ECD letter for the review to continue. If there are major problems such as significant amount of information missing, then an IR (Information Request) letter will be sent to the company, the company will have 30 days to respond.
4. I will then check the FDA current guidance regarding the specific drug to see what type of, and the number of studies required. Are both the parent and metabolites pharmacokinetic parameters stipulated in the bioequivalence criterion? Any special comments about how the study should be conducted? In special population of subjects?
5. Then the real fun begins, it’s data analysis time. The primary criterion for bioequivalence between the test and reference is 90% confidence interval between 80.00 to 125.00%. When a study is marginal (i.e. when the 90% CI falls between 83.00-120.50%) then I will re-analyze data to confirm the results presented by the company.
6. Next, I will examine the incidents of adverse events during the clinical studies. Were the adverse events observed in the clinical study the same ones as those in patients whom have taken the referenced drug previously? Are the number and severity of the adverse events similar between the test and reference drug products? Were there any life-threatening adverse events? How and when did the adverse event resolve? If there are severe adverse events, then I will send a clinical consult to the medical division for them to evaluate the impact of the adverse event on the outcome of the study.
7. Next, how many subjects dropped out of the study? Why? Should their result be included in the study analysis? Is the study still statistically significant?
8. I will also look at how the blood samples from the clinical studies were analyzed. Were there any irregularities such as sample concentrations over the standard or quality control concentrations? Were the internal standards valid? How did the company explain these irregularities? Were there samples that need to be reassayed? Were the reassayed procedures adequate and pre-established?
9. Then I will look at the formulation of the test drug product in comparison to the referenced drug. Most of the time, companies will have to reverse engineer the innovator drug to figure out what is in their formulation, so the ingredients in the test drug product might not be precisely the same as in the reference drug. If the amount of ingredients is not the same, then what are the possible impacts of these differences? I might need to send out a consult to another division to ask for their opinion.
10. The above is a selected list of tasks, there are many more included in a complete review. When I complete the review, I forward it to the secondary reviewer, who will check the review for accuracy, and see if there is anything else missing before the review is sent to the tertiary reviewer for final approval.
There are meetings within the division and with other divisions to discuss any issues from the review. There are also many opportunities to participate and learn about different therapeutic areas and drug categories.
In my next blog I will discuss the work environment at the Office of Generic Drugs at the FDA.
