# Presentation: 322618

## Paula M. Jacobs, Ph.D.
SAIC Frederick
Cancer Imaging Program/DCTD/NCI/NIH  
September 5, 2006
Phase 0 Trials in Oncologic Drug Development 

**SAIC Frederick**
**Cancer Imaging Program/DCTD/NCI/NIH  **
**September 5, 2006**
**Phase 0 Trials in Oncologic Drug Development**** **

**DCTD Phase 0 Workshop**

**Nuts and Bolts:****You Too Can Prepare an IND**

## Overview of Early Development

**Synthesize a number of new imaging drugs**
**Evaluate them in pre-clinical settings**
**Pick the best ones to test in humans**
**Learn to prepare them consistently**
**Perform *****in vivo *****pharmacology and toxicology in appropriate animal models**
**Chose initial dose for human studies: least risk**
**Assemble the data and submit to FDA or to your RDRC**
**Obtain IRB approval**
**Test in human subjects**

**Notes:**
Here is what you need to do to develop and test a new imaging agent.  The process is identical for therapeutic agents and for traditional IND vs. exploratory IND.  Only the extent of require data are different.

I’m not going to talk much about the science here, I am going to talk about the regulatory process – but I promise not to read 21 CFR to you 

Typically, several candidate molecules are generated in small quantities with the goal of identifying the most promising candidates for further development. These molecules are generally related in some way, either as a single active ingredient with multiple salts or esters, or closely related compounds for the same target.
Promising candidates are then selected using in vitro testing models that examine binding to receptors, effects on enzyme activities, toxic effects, or other in vitro pharmacological parameters.  Candidates are then prepared in greater quantities for in vivo animal testing for safety and efficacy.
For a traditional IND, a single candidate is selected for an IND and testing in human subjects, often healthy volunteers. 
For an exploratory IND, a family of candidates can be included, allowing selection based on human response

## Approach to Regulatory Requirements

**Regulations are the same for**
**Labeled therapeutic agents**
**Functional imaging agents**
**General imaging agents**
**Development strategy may differ with goal**
**Basic information about a therapeutic**
**Basic information about a tumor**
**Imaging for evaluating response to therapy**

**Notes:**
The approach to getting regulatory permission to study an experimental imaging drug in humans depends on both the intent of the initial studies in humans and on the expected final use of the imaging drug.
Basic information about a therapeutic agent, such as adsorption, distribution, metabolism and excretion can be obtained from a labeled therapeutic drug and no further imaging may be intended
Basic information about a tumor, using functional imaging drugs, may or may not be intended to be part of routine staging or evaluation of response to therapy

## Investigational Clinical Trials

**The sponsor must apply for permission to study drugs in humans **
**From FDA for IND – traditional or exploratory**
**From the Radioactive Drugs Research Committee (RDRC) at your institution**
**From an IRB for either**
**“****Sponsor”**
**Individual physician**
**Institution**
**Industry**

**Notes:**
If a drug is not approved for marketing, it must be studied in humans under an IND. Imaging agents are regulated as drugs, just like therapeutics. However, because medical imaging agents are used solely to diagnose and monitor diseases or conditions as opposed to treat them, development programs for medical imaging agents can be tailored to reflect these particular use.
 Radioactive drugs can also be studied under an RDRC and Dr. Shields will discuss this next
Note that this is not necessarily all – you may also be required to obtain the approval of your cancer center, your department, CTEP
“Sponsor” is the individual investigator, institution, or company proposing to study a new drug.

## RDRC vs. IND

**RDRC: for basic research only**
**E.g., kinetics, distribution, dosimetry**
**NOT safety or efficacy**
**Pediatric studies restricted**
**Only small doses and few patients**
**Drug must have been in humans before**
**IND: not restricted to basic research **
**Can study safety and efficacy (i.e., clinical trials)**
**Can do basic research**
**Pediatric studies less restricted**

**Notes:**
RDRC
The labeled drug needs to be one that is chemically identical to a drug that has been tested in humans—newly reinforced by FDA
Why would you choose the IND if you can do an RDRC? 
further plans for research that would require an IND, such as needing higher radiation dose to get imaging data.  
Intent to use the agent to stratify patients or to evaluate response to therapy
Intent to study more than 30 patients

## Types of IND

**Three types of traditional INDs:**
**An investigator initiated IND**
**Emergency use IND (E-IND)  **
**Treatment IND**
**And a new type:**
**Exploratory (“phase 0”, x-IND)**

**Notes:**
Investigator initiated IND can come from a single physician investigator, a company, an institution, or a government agency.  All are “sponsors”
E-IND allows the FDA to authorize use of an experimental drug in an emergency situation for a single patient
Treatment IND allows experimental drugs showing promise in clinical testing for serious or immediately life-threatening conditions to be used while the final clinical work is conducted and the FDA review takes place. (Compassionate Use IND)

X-IND Why a new kind of IND:  
Fewer than 10 percent new molecular entities (NME) progress beyond the investigational stage 
Traditional pre-clinical data packages for IND are very expensive and time-consuming.  These early safety tests are usually resource intensive, requiring significant investment in product synthesis, animal use, laboratory analyses, and time. Many resources are invested in, and thus wasted on, candidates (including imaging agents) that may eventually be found to have unacceptable profiles when evaluated in humans.
Animal testing does not always predict performance in humans  - the experience of the immunomodulatory drug TGN1412 in March 2006 in the UK proved that.  In its first human clinical trials, in March 2006, it caused catastrophic systemic failure in the subjects, despite being administered at a dose of 0.1 mg per kg, some 500 times lower than the dose found safe in animals,[3] resulting in the hospitalization of six volunteers with multisystem organ failure

## What’s the difference?

**Traditional**
**Single agent**
**Plans for Phase 1, 2, 3 trials and NDA**
**Extensive pre-clinical data needed to begin**
**Dose escalation, therapeutic evaluation **
**Exploratory**
**Multiple agents under one IND, go/no go**
**Microdose, first in man studies**
**No therapeutic intent **
**Biodistribution, pharmacokinetics, safety**
**Less pre-clinical data required**
_**Resubmit as Traditional IND if successful**_

**Notes:**
The traditional IND is for a drug expected to go through the entire process to eventual drug approval
The exploratory IND allows low dose first in man studies that will study safety,  pharmacokinetics, pharmacodynamics, and make go/no go decisions – rather similar to the RDRC process, but does not have to be radioactive. Microdose ≤100 μg or 1/100th of pharmacologically active dose
If successful and further extension to higher doses and phase 2 studies, it would be resubmitted as a traditional IND.  This is important to note, as the x-IND does not give you a pass on the pre-clinical data needed, it just delays some of it.

## FDA Guidance on the IND process with multiple links to other documentation:
http://www.fda.gov/cder/regulatory/applications/ind_page_1.htm
Comprehensive FDA Guidance Page
http://www.fda.gov/cder/guidance/guidance.htm 
An “how-to” guide from the Biological Development Program at NCI-Frederick with multiple links
http://wwwbdp.ncifcrf.gov/pdf/GuidetoRegSubs.pdf
Schedule a pre-IND meeting 

_**[http://www.fda.gov/cder/regulatory/applications/ind_page_1.htm](http://www.fda.gov/cder/regulatory/applications/ind_page_1.htm)**_
**Comprehensive FDA Guidance Page**
_**http://www.fda.gov/cder/guidance/**__**guidance.htm**__** **_
**An “how-to” guide from the Biological Development Program at NCI-Frederick with multiple links**
_**[http://wwwbdp.ncifcrf.gov/pdf/GuidetoRegSubs.pdf](http://wwwbdp.ncifcrf.gov/pdf/GuidetoRegSubs.pdf)**_
**Schedule a pre-IND meeting **

**Where to get information**

**Talk to the FDA!**

## Nuts and Bolts of an IND

**What data are needed**
**What supporting information is needed**
**How is the application put together**
**What happens when it is submitted**

## Information Required in INDs

**Pharmacology/toxicology in animals**
**Dosimetry for radiopharmaceuticals**
**CMC: Chemistry, Manufacturing and Controls **
**Some of these data may be referenced from existing INDs or the literature**
**Clinical Information****  **

**Notes:**
Preclinical data to permit an assessment as to whether the product is reasonably safe for initial testing in humans.  Any previous experience with the drug or chemically related drugs in humans. 
Information pertaining to the composition, manufacturer, stability, and controls used for manufacturing the drug substance and the drug product.
Can use Letters of Authorization (cross-file letters) if there is an existing IND held by a friendly party and/or a DMF held by a supplier

## Clinical Protocols and Investigator Information 

**Detailed protocol for clinical study **
**Qualifications of clinical investigators **
**Commitments **
**To obtain informed consent **
**To obtain review of the study by an institutional review board (IRB)**
**To adhere to the investigational new drug regulations **

**Notes:**
Detailed protocols for proposed clinical studies to assess whether the initial-phase trials will expose subjects to unnecessary risks.  
Information on the qualifications of clinical investigators (generally physicians) who oversee the administration of the experimental compound
Commitments to obtain informed consent from the research subjects, to obtain review of the study by an institutional review board (IRB), and to adhere to the investigational new drug regulations.

## IND Application

**1.  Form 1571 (Application)**
**2.  Table of Contents of Application **
**3.  Introductory Statement**
**4.  General Investigational Plan **
**5.  Investigators’ Brochure (multi-site)**
**6.  Protocol**
** ****Study Protocol**
** ****Investigator Data – Form 1572, CV**

**Notes:**
These are the elements you must include in the IND – include them all and don’t change the order.  
Introductory statement- 3-6 pages.  Overview, include info on drug, rationale, trial, future plans
On the form 1572, note that all individuals involved with the care of the patient should be listed on the form. Include nurses, for example, but not radiochemist.  Rule of thumb:  everyone who physically touches the patient

## IND Application

**  ****7.  Chemistry, Manufacturing, and****    Control Data**
**  ****8.  Pharmacology and Toxicology Data**
**  ****9.  Previous Human Experience**
** ****10. Additional Information.**
**Dosimetry**
**Letter from IND or DMF-holder allowing cross- reference to their files**
**Site/NCI Data and Safety Monitoring Plan**
**Cited literature **

**Notes:**
For most non-industry applicants (and many of those!), the CMC section is often deficient.

## Practical Issues

**Make it easy for multiple reviewers to find and understand the information – repeat information in different sections**
**Include all sections, even if empty**
**Comprehensive Table of Contents and TOC for any section more than a few pages**
**Consecutive page numbers for entire IND (can be numbered by section )**
**Include copies of all cited literature**
**Don’t assume the reviewers will be expert in your subject area**

**Notes:**
I shouldn’t have to include this slide, but experience tells me otherwise
The FDA will break up the submission and give different parts to different reviewers.  MAKE SURE ALL SECTIONS ARE SELF EXPLANATORY!
Note that you should include all of the items in the 1571, in this exact order.  Missing sections will delay your submission.  If an item is not needed, include the section and say not applicable

## What happens next?

**Submit 5-15 copies (ask FDA Division)**
**Wait 30 calendar days before beginning the first study on IND**
**The document goes to several reviewers**
**FDA reviews the IND first and foremost for risk to subjects – NOT for scientific interest**
**FDA may request changes**
**Safety related in protocol**
**Purity/safety related in CMC**
**FDA will call/fax with questions**

**Notes:**
Make extra copies!!! FDA often asks for more

Remember in this process that FDA is neither your friend or your enemy, but that they all review a large number of applications under strict deadlines. They have seen some 

## Begin your investigational study in human subjects

- _[jacobsp@mail.nih.gov](mailto:jacobsp@mail.nih.gov)__ _

- Thanks for your atttention

## The Next Speaker is:Dr. Anthony Shields

**The Next Speaker is:****Dr. Anthony Shields**