Q & A by Dr. Wise Young

Posted on Cure Forum @ CareCure.org October 02  2012

Difference between simplified and scientific look @ Human Trials to Cure Spinal Cord Injury

Question posted by me:

comad's Avatar

Question for Doctor’s & Scientists.

Can you use and how fast you can use other team or scientist research?

For example – I have a feeling that Dr.Wise need something to clear path on “scar tissue” for all stem cells to better connect. Possibly, that’s why the Cethrin [that was proven to be safe and relatively effective in Human acute trial and can get safety approval on chronic rats] is in the game. 
For Dr. Silver’s research on method of Cha’se delivery – there is longer path till comes approved to Human trials if shows effective on chronic injured rats and he and his team can definitely use already organized Human trial network by SCiNEt to speed up the whole thing.
I have feeling that mixing up of those 2 will accelerate everything to the point of having cure within 2 years from now.
However, as collaboration of 2 teams is out of this world and X prize is nowhere on horizon is there any way that one scientist can use results and method’s from another scientist and include in his research / trial?

Answer posted by Dr. Wise Young:

Comad,

To take a therapy to clinical trial in most countries around the world, one must get regulatory approval from the FDA in the United States, the EMA in Europe, the sFDA in China, or various departments of health in other countries. The information used to support the trial does not necessarily have to be published (although peer-reviewed information is generally more credible and impressive) before submission to the regulatory agencies.

The FDA and most regulatory agencies carefully scrutinize any first-in-human drug trials. The treatment must fulfill several strict criteria before an IND (investigational new drug) application is approved. The following are some information that must be provided in the IND application.

1. The FDA requires safety data from one large animal and one small (rodent) animal species, collected under GLP (Good Laboratory Practice) conditions.

2. The trial sponsor must provide detailed data about pharmacokinetics (time course of the drug in the blood) and pharmacodynamics (time course of the drug in the tissue of interest).

3. Information about efficacy or at least rationale for efficacy must be provided.

4. The drug manufacturing method, potency, shelf-life, purity, must be provided. documentation of GMP (Good Manufacturing Practice) must be provided.

5. Based on the product manufactured under GMP conditions, secondary metabolic products, and any side-effects from secondary metabolic byproducts must be studied and described in detail from animal studies.

There is a fallacy amongst inexperienced scientists that efficacy data in animal studies are required or sufficient for IND approval. The first and most important criterion for IND approval is safety. In order to evaluate safety, the FDA must have as much information about the drug as possible to understand the risk that the drug and its secondary metabolic byproducts may pose to human subjects. They must confirm that the drug is being manufactured under GMP conditions (where all procedures and reagents are rigorously documented) and the safety studies are being done under GLP conditions (where all aspects of the rats and the studies are being properly documented).

Animal efficacy data is of course helpful but, when it is not available, therapeutic rationale is often sufficient, if the treatment is safe. Many therapies cannot be tested in animals. Credible rationale for efficacy is often sufficient to allow IND approval. All lot of scientists have focused on showing efficacy in animal studies and then don’t do all the other studies that are necessary to obtain IND approval. As a result, few treatments ever go to clinical trial. If a drug company doesn’t take the responsibility and expense of carrying out the safety and manufacturing studies, the treatment seldom goes to trial.

Cethrin is a very good example of how a drug is developed from spinal cord injury. I have long been a strong supporter of Lisa McKerracher and her passionate approach to getting Cethrin into clinical trial. After she discovered that C3 (a bacterial toxin that blocks rho) has some effects on spinal cord regeneration, she formed a company called Bioaxone to develop the drug further. She soon found that the drug doesn’t get into the nervous system as well needed to stimulate regeneration and therefore modified the C3 toxin by appending a transport sequence to the molecule so that neurons would pick it up, calling this new molecule Cethrin. She then did all the animal studies showing that this drug works, raised about $15 million to get all the safety studies and GMP manufacturing of the drug established, and took it to Phase I/II clinical trial in 48 patients with spinal cord injury. The study showed impressive (although not controlled) benefit for the patients, compared with historic recovery of patients with ASIA A. Over 60% of cervical spinal cord injury patients converted from ASIA A to ASIA C, for example.

The task of taking the treatment to phase III trial is a daunting one and Lisa sold the license for Cethrin to Boston Life Sciences (BLS), which changed its name to Alseres. This coincided with the 2008 stock market crash and Alseres was unable to raise funding for the phase III trial, returning the license to Lisa McKerracher last year. She re-formed Bioaxone in the United States and is now raising the money for the phase III trial. Cethrin is a drug that has been shown to be safe in human and has had promising results in phase I/II studies in the United States and Canada. Despite this, she is having trouble raising the money for phase III trials in the United States and therefore have turned to Asia.

Regarding chondroitinase, Acorda Therapeutics is working on safety and other studies necessary to get chondroitinase ready for IND approval. They have some studies that still have to be done, including GMP manufacturing of the drug and pharmacokinetics and pharmacodynamic studies of different routes of administration. If Jerry Silver has a small molecule that can block the CSPG receptor, this would essentially scoop chondroitinase as a potential therapy for spinal cord injury. So, you can imagine how this does not necessarily encourage Acorda Therapeutics to invest millions of dollars into doing more safety studies of chondrotinase in animal spinal cord injury models. Nevertheless, Accorda is doing so, perhaps because it will take time and expense to move a first-in-human drug into clinical trial.

ChinaSCINet must make sure that therapies are ready for trial before it can do the trials. As much as I would like to take chondroitinase and other therapies to trial, it must fulfil the criteria required for regulatory approval. Otherwise, we cannot take the treatment to trial. I not only have to ensure that a treatment will receive regulatory approval but I must convince 25 principle investigators in ChinaSCINet to devote the time and resources to testing a treatment. This is one of the reasons why I hold many meetings in China, from workshops to symposia. ChinaSCINet has an important educational role as a clinical trial network.

This is also true of any company or sponsor trying to get a therapy to trial. One must not only convince the regulatory agency but also the investigators. Sure, some companies can shell out millions of dollars to investigators, who then become hired hands. I assure your that ChinaSCINet does not have this kind of money or aspiration. The network decides on the most promising therapies to test. All investigators in the trial •volunteer• their time to operate on the patients and to take care of them. They must be convinced of the therapeutic promise and safety before they will embrace the trial.

Wise.

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