Wednesday, July 28, 2021

FDA Regulatory Education for Industry (REdI) - Learning about FDA and Regulatory Science

FDA had their annual conference “FDA Regulatory Education for Industry (REdI)” last week. The REdI conference features three medical product center tracks: Drugs (CDER), Devices (CDRH), and Biologics (CBER). 

The recorded presentations by different tracks (drug, device, biological,...) are available on FDA's website and the conference agenda for this 5-day event is listed here

REdI presentations provide opportunities to learn directly from the FDA’s regulatory experts in medical product centers: drugs, devices, and biologics. This course is designed to provide participants with a strong, basic foundation in the FDA’s regulatory requirements.

The recording of the REdI conference are also posted on Youtube and separated by days 1 - 5.

Day 1: 


Day 2:

Day 3:

Day 4: 

Day 5: 

In Day 1 presentation by Dr. Bugin, the reorganized structure for various divisions under the Office of New Drug (OND) is revealed. 

Sunday, July 25, 2021

Maximum Tolerable Dose (MTD) and Dose-Limiting Toxicities (DLTs)

According to Wiley Encyclopedia of Clinical Trials, the maximum tolerable dose (MTD) is defined as: 

The “Maximum Tolerable Dose” (MTD), also known as the “Maximum Tolerated Dose” or the “Maximally Tolerated Dose”, is defined as the dose that produces an “acceptable” level of toxicity or that, if exceeded, would put animals or patients at “unacceptable” risk for toxicity. Besides determining animal toxicology, establishing the MTD is the main objective of Phase I clinical trials, mostly in cancer and HIV treatment in which relatively high doses of drugs are usually chosen to achieve the greatest possible beneficial antitumor effect. Definition of the MTD usually relies on the sample, as MTD is defined as the dose level at which more than two patients over six experienced dose-limiting toxicity (DLT). More recently, the MTD has been defined as the dose that produces a certain frequency of DLT within the treated patient population. In this framework, the MTD is estimated from the data using Bayes or maximum likelihood inference. In all these designs, the MTD is established for one initial administration or treatment course of a cytotoxic experimental agent, ignoring efficacy. To address these issues, the maximum tolerated schedule and the most successful dose have been proposed to be used rather than a conventional MTD. Finally, the concept of MTD that uses toxicity as a surrogate endpoint for efficacy in cytotoxic Phase I trials has been also controversial. Interests in alternatives to MTD have gained recently when dealing with new cytostatic agents that may produce relatively minimal organ toxicity, compared with standard cytotoxics. New optimal doses should be defined in the near future.

The clinical trials with the objective of determining the MTD are designed as dose-escalation studies with patients enrolled into the low dose group and then gradually into the high dose group. The patients who are enrolled under the same dose level below to the same dose cohort. The determination of the MTD relies on the identification of the dose-limiting toxicities (DLTs). Prior to escalating the dose cohort, the safety and tolerability in the previous cohort will be assessed and evaluated. 

According to NCI, DLTs are defined as side effects of a drug or other treatment that are serious enough to prevent an increase in dose or level of that treatment. In early-phase clinical trials, DTLs are defined so that the escalation of the dose cohort to the higher dose level can be determined based on the observed # of DTLs, which are subsequently used to determine the maximum tolerable dose (MTD). 

The dose-escalation study for determining the MTD is the most common first-in-human study design in oncology studies. The DTLs are usually defined as grade 3 or above drug-related adverse events defined by the common toxicity criteria for AEs (CTCAE) maintained by the National Cancer Institute (NCI). 

In non-oncology studies, the CTCAE criteria can still be used to define DTLs. But we also see some non-oncology studies with the customer-defined DLTs criteria.

Here are some examples of how the DTLs are described in oncology clinical trials with MTD as the purpose.  

A Multicenter Phase I Gene Therapy Clinical Trial Involving Intraperitoneal Administration of E1A-Lipid Complex in Patients with Recurrent Epithelial Ovarian Cancer Overexpressing HER-2/neu Oncogene

Toxicity during therapy was categorized as unrelated to, probably, possibly, or definitely related to E1A lipid complex. The dose-limiting toxicity was defined as the highest dose at which at least 2 of the 6 patients experienced National Cancer Institute Common Toxicity Criteria grade 3 or 4 drug-related toxicity during the course of therapy. Maximum tolerated dose was defined at one dose level below dose-limiting toxicity

Intra-arterial administration of a replication-selective adenovirus (dl1520) in patients with colorectal carcinoma metastatic to the liver: a phase I trial
Dose escalation proceeded from 2 × 108 to 2 × 1012 particles without occurrence of any dose-limiting toxicities. Specifically, no treatment-emergent clinical hepatotoxicity occurred during dose-escalation, despite pre-existing liver abnormalities due to intrahepatic metastases in over half of the patients at baseline. Transient low grade (1– 2) transaminitis was documented in three patients (following single agent virus) and was classified by the investigator as ‘possibly attributable’ to ONYX-015 (6 × 1011 and 2 × 1012 particles); the laboratory abnormalities resolved within 12 days and did not reoccur after subsequent treatments. Four patients had liver-related adverse events reported (hyperbilirubinemia) that were classified as ‘unrelated’ to ONYX-015 and were associated with intrahepatic tumor progression. The highest dose administered (2 × 1012 particles) was shown to be well-tolerated in three patients. The 2 × 1012 particle dose level therefore appears to be well-tolerated, and the maximum dose that could be administered based on manufacturing capabilities was the MTD for the study

Redefining Dose-Limiting Toxicity

Dose-limiting toxicities (DLTs) traditionally are defined by the occurrence of severe toxicities during the first cycle of systemic cancer therapy. Such toxicities are assessed according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) classification, and usually encompass all grade 3 or higher toxicities with the exception of grade 3 nonfebrile neutropenia and alopecia. This broad definition dates back to the development of conventional cytotoxic chemotherapeutic agents, and is not applicable to the toxicity profile of modern molecularly targeted therapies (MTTs), which now constitute the vast majority of drugs evaluated in phase 1 trials. Despite this shift in drug development, the old definition of DLT is still used for most clinical trials. However, a few clinical trials are beginning to update their definition of DLT, and now tend to add variations to that common DLT definition backbone. The most frequent changes include the addition of some a priori untreatable or irreversible grade 2 toxicities (eg, neurotoxicities, ocular toxicities, or cardiac toxicities), prolonged grade 2 toxicities (ie, grade 2 toxicities lasting longer than a certain period), or the prolongation of the DLT period. However, these changes are still rare and most phase 1 clinical trials still use the traditional DLT definition.

Lenalidomide in Treating Patients With AIDS-Associated Kaposi's Sarcoma
Toxicities will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. Using a 3+3 design, the MTD is defined as the level at which 0/6 or 1/6 patients experiences at dose-limiting toxicity in the first cycle.

Here are some examples of how the DTLs are described in non-oncology clinical trials with MTD as the purpose.  

The LIPid Intensive Drug Therapy for Sepsis - Pilot (LIPIDS-P) Phase I/II Trial
LIPid Intensive Drug therapy for SepsisPilot (LIPIDS-P): Phase I/II clinical trial protocol of lipid emulsion therapy for stabilising cholesterol levels in sepsis and septic shock

Safety and Tolerability Study of Allogeneic Mesenchymal Stem Cell Infusion in Adults With Cystic Fibrosis (CEASE-CF)

Dose limiting toxicity (DLT), triggered by occurrence in the first 24 hours after hMSC infusion of grade ≥3 infusion-related allergic toxicities [ Time Frame: 24 hours ]

 Phase 1b Study of PD-0332991 in Combination With T-DM1(Trastuzumab-DM1)

Toxicity will be assessed using the Common Terminology Criteria of Adverse Events (CTCAE) version 4.0 grading scale. Dose- limiting toxicity-DLT is defined as any drug-related grade 3 non-hematologic toxicity or grade 4 hematologic toxicity lasting >28 days after the last day of therapy. If two patients experience drug-related DLT, the maximal tolerated dose (MTD) for the combination in HER2-positive breast cancer patients has been exceeded, enrollment to that dose will stop, and the next lower dose will be designated the MTD. An additional 15 patients will be treated at the MTD or the maximal 200mg po daily PD-0332991 dose in combination with T-DM1 to confirm safety. Treatment cycles will continue until disease progression or withdrawal from study.
Histone Deacetylase Inhibitor LBH589 in Addition to Corticosteroids in Patients With Acute Graft Versus Host Disease (GVHD)
Dose limiting toxicity (DLT) is defined by the occurrence of Common Toxicity Criteria (CTC) grade 3 or greater toxicity that is unexpected with transplantation, except for hematological toxicity, where DLT is defined as absolute neutrophil count (ANC) <750, and for those participants who were platelet transfusion independent is defined as platelets <10 K.
We can identify the clinical trials on with the purpose of identifying the MTDs and DLTs. The vast majority of these studies are oncology studies or studies in serious conditions - these studies are usually conducted in patients (not healthy volunteers) and must be registered on even it is a phase I study - the phase I studies in healthy volunteers are exempted from the registration. 

Sunday, July 18, 2021

Imputation of partial dates for adverse events, concomitant medications, and disease diagnosis

Many date variables are collected in the clinical trial database. The date variables include date of birth, date of disease diagnosis, date of medical history onset, start and stop date of adverse events, start / stop date of concomitant medications, ......

It is not uncommon that the partial dates may be collected where the partial dates mean that at least one of the components (day, month, or year) is missing. 

Partial date for date of birth is not because the subjects don't remember their birth date, is because the data security law prevents the sponsors from collecting the date of birth information in certain countries (especially in Germany). 

In statistical analyses, the partial dates need to be handled or imputed for the purpose of allocating the event (adverse events, concomitant medication) into the appropriate categories (treatment-emergent adverse events, prior medications, concomitant medications added during the study,...) or calculating the duration of the events (duration from the disease diagnosis to the study start).

For clarity, the algorithm and rules for imputing the partial dates need to be specified in the statistical analysis plan (SAP). There is no regulatory guidance about which algorithm and rules will be appropriate when imputing the partial dates. Different companies may have different rules when imputing partial dates. In general, the rules will be adequate as long as it is on the conservative side, for example, if an adverse event has a partial or missing start date and can't be determined if it occurs before the first dose of the study drug, the adverse event will be classified as 'treatment-emergent adverse event'. 

Partial date imputation is always a single imputation - the missing day or missing month will be replaced with a fixed day or month based on the imputation algorithm. The candidates for replacing the missing day could be: the first day of the month, the last day of the month, the day of the first dose of the study drug. The candidates for replacing the missing day and month could be Jun 30 of the year or July 1 of the year. 

Usually, if all day, month, and year are missing, the missing date will not be imputed. The adverse events with missing onset date will be classified as 'treatment-emergent AEs' and the concomitant medication will be classified as 'on treatment medications' (i.e., to be included in summaries of concomitant medications during the study). 

Below are a list of algorithm and rules for imputing the partial dates for adverse events and concomitant medications:

In an SAP for a Pfizer phase I study, if the day of the month is missing, the 1st day of the month is used. 

In a Novartis study SAP, the rather complicated algorithm was proposed for imputing the partial dates for adverse events and concomitant medications:

In a study by Johnson & Johnson, the appended SAP specified the rules for imputing the partial dates for adverse events, concomitant medications, and for disease diagnosis as the following: 

In a study by ChemoCentryx in NEJM, the appended SAP described the imputation rules for partial dates for adverse events and concomitant medications as the following: 


In the paper "Partial Dates; decisions and implications of handling partially missing dates" by Bowman, the following rules were stated for imputing the partial dates for adverse events and concomitant medications. 

Missing Adverse Event Start and Stop Dates date:

There are two options available. The partial start date may be set to the first of the month or to equal the study medication start date. As previously discussed, the first option would indicate the adverse event began prior to the study medication. However, the second option, setting the start date of AE1 to the study medication start date will suggest the adverse event had a short duration, as the adverse event end date is also defined as June 2006, but began during the treatment period of the study drug. Although the second option is not ideal, as AE1 may have had a longer duration, it is more conservative to associate the adverse event start with a date during study medication. Another solution to consider is not to impute a date at all but merely to assign a study phase to the start of the adverse event. In this example, a phase of "treatment" could be allocated to the start of teh adverse event, which would ensure it was classed most conservatively, without defining an actual date to the start of the adverse event. 

Concomitant Medications:

Subject has a partial concomitant medication start date of “--Apr2006” (see figure 1). As discussed above, missing start dates may be set to the first of the month, which is shown under option 1. However, this then pushes the concomitant medication to starting before the first dose of the Study Medication (15Apr2006) and would suggest that the Study Medication had no involvement with the concomitant medication being taken. Is this really the most conservative approach? If not is there an alternative? The missing concomitant medication start date could be set to equal the first dose of Study Medication, options 2. This option allows the concomitant medication to be classed as an on-treatment medication, and is therefore the most conservative.  

Monday, July 12, 2021

Human Plasma-derived Products - Protein Therapies for Rare Diseases

I recently listened to a podcast from NPR's planet money "Blood Money". It discussed why only the U.S. and a few other countries allow companies to pay people for blood (or precisely the plasma) - the materials for many life-saving protein therapy products for rare diseases. Please listen to the podcast or read the transcripts of the podcast. 

Blood Money

We all heard or experienced blood donation which is usually voluntary by the donor with no monetary incentives. The Plasma donation is different and donors are paid for donating their plasma. So the first question we need to know what the difference between the (whole) blood and the plasma. Here is a table for comparison:

Whole Blood


This red bodily fluid is composed of red cells, white cells, plasma, and platelets. It supplies oxygen and essential nutrients to cells and tissues in the body and removes waste materials like carbon dioxide and lactic acid.Plasma is the clear, straw-colored liquid component found in the blood. It is made up of 90% water and carries nutrients, minerals, hormones, and proteins to parts of the body that need it. Plasma also contains antibodies that help fight infections and proteins including albumin and fibrinogen that help maintain serum osmotic pressure.
With red cells, white blood cells, and platelets in itWith red cells, white blood cells, and platelets removed


plasma is collected through a process known as plasmapheresis. Plasmapheresis is a method of removing and separating plasma from whole blood via an apheresis machine.

After Plasma is separated from the whole blood, the red blood cells and other cellular components are returned to the doner’s body
Whole blood is commonly transfused in its original form in an effort to treat injuries and illnesses. It can be also be separated into its individual components and used to treat conditions including cancer and blood disorders.Plasma, on the other hand, is typically used as a starting material to manufacture commercial drugs known as plasma-derived products. These plasma-derived products serve as lifesaving therapies for patients living with immune deficiencies and autoimmune diseases.

Human plasma is a treasure and contains many enzymes and antibodies that can be extracted and manufactured as medicines for many rare diseases. Human plasma products (also called plasma-derived products or fractionated plasma products) are highly regulated by the FDA - Office of Blood Research and Review under the Center for Biological Evaluation and Research (CBER). The drugs manufactured from human plasma (so-called plasma-derived products) need to go through the same process as other biological products and Biological License Application (BLAs) needs to be approved by the FDA for market authorization. Human plasma-derived products have been approved to be used in treating diseases in various indications in immunology area, enzyme replacement/augmentation therapies, neurology, pulmonary, hemostasis, ...... Some examples are:

  • Alpha-1 antitrypsin deficiency (A1AD)
  • Primary Immunodeficiency (PI)
  • Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)
  • Guillain-Barré syndrome (GBS)
  • Hemophilia
  • Rabies
  • Hepatitis B
  • Kawasaki disease

The blockbuster product from the plasma fractionation is immunoglobulin (IVIG or SCIG). immunoglobulin is a life-saving product for primary immunodeficiency patients. Immunoglobulin is also thought to be a panacea for all kinds of neurological diseases (CIDP, GBS, Myasthenia Gravis, multifocal motor neuropathy) that some of which have no other efficacy treatments. 

Many of these diseases treated with plasma-derived products are orphan diseases or ultra-orphan diseases.

Theoretically, plasma-derived products have a risk of carrying bloodborne pathogens (viruses and other pathogens). However, these pathogens are destroyed or filtered out during the manufacturing process. The actual plasma-derived products are very safe - at least in the United States. 

For clinical trials with plasma-derived products, the following points are noted: 

  • Similar to the oncology drugs, the plasma-derived products can not be tested in healthy volunteers. Even for the first-in-human trial, the plasma-derived products will need to be tested directly in the patients.  
  • The study procedure will always need to include the virus tests at screening and possibly the following up visits. 
  • Always include the immunogenicity assessment (because the plasma-derived products are large protein therapies)
  • The design and analyses of clinical trials are the same as other drugs or biological products. For ultra-rare diseases, the single-arm design may be used as the pivotal study and the sample size can be very small. See FDA Approves First Ever Treatment for Plasminogen Deficiency Type 1 based on a single-arm study with 15 adult and pediatric patients with plasminogen deficiency type 1.
  • For pharmacokinetic analysis, the pre-dose drug concentration is not zero since there are endogenous compounds (i.e., enzymes or antibodies that are generated by the patients). 

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