Johnny Member wrote:
I just read this summary of AOD which I thought was interesting....
Whilst AOD9604 is not approved by the Australian TGA, it can be legally obtained on a doctor's prescription and dispensed by a compounding pharmacy (2). This is true of many experimental substances, but it does big favours for the reputation of AOD9604, giving the impression that, like other drugs issued by the medical profession, it is an efficacious and high quality product.
Metabolic turned their attentions to human studies, and performed six clinical trials on 925 people between 2001 and 2007. Not one of these trials showed that AOD9604 caused any weight loss or changes in body composition (3). In 2007, the company that owns Metabolic, Calzada, reported to their shareholders that AOD9604 showed no promise, and was being abandoned as a weight loss drug (2,3). The failure was blamed on inefficient absorption of the peptide drug through oral administration, as was used in the trials, even though rodent studies had shown the oral delivery route to be effective. At this point, Metabolic had sunk a massive $50 million into development and trials of AOD9604.
If there's one thing that science has definitively said about AOD9604, it is that it is safe and has no side effects. Calzada, after trying the peptide out as an anti-obesity and anti-arthritic, has succeeded in having the peptide declared "Generally regarded as safe" by the FDA, which makes it legal to use as a food additive in America. Calzada, seemingly under no pretense that their product has pharmaceutical properties, is now trying to break into the US over the counter supplement and "Nutraceutical" market with AOD9604 (2,4).
Interestingly, the compound has only been approved for use in levels of up to 1mg per day (2), whereas the doses used in trials generally hovered around 500ug/kg (5,6), which means a 100kg person was receiving 50mg of the peptide daily. There is no science behind the peptide, or the dosage, and Calzada themselves have previously said AOD9604 is not effective orally (2).
The above are excerpts. But if you were looking for a conspiracy, you could read into it that they'd pulled the pin on AOD because taking it orally simply didn't work. But their ears pricked up when they found out bodybuilders were buying it from overseas. One guess at how a bodybuilder would take it?
I was tidying up my downloads this week, JM, when I came across a swag about AOD from a while back. Here's a bit of one from the tail end of a paper on it's effect on mice (seeing you named that very rodent):
"The results presented in this paper suggest that
the effectiveness of AOD9604 and hGH may partly rely on
their ability to increase levels of 3-AR RNA expression in
models of obesity in which the numbers of the lipolytic
receptor are low. These unique properties may give
AOD9604 an advantage over other lipolytic agonists such as adrenergic agents and hGH, which exhibit undesirable side
effects when administered chronically"
One of the authors of that paper was Ezra Ogru. Calzada had very strong ties to a company named Phosphagenics, including a lot of personnel transfers. Ezra Ogru was the CEO of Phosphagenics. This was her lot as her time came to an end:
http://www.smh.com.au/business/six-year ... 1irt9.html
I do love me a good refresher. From another download, this time an ASX announcement from Metabolic before Calzada took them over:
"Melbourne, 21 February, 2007. Metabolic Pharmaceuticals Limited (ASX: MBP) announced today that
the Phase 2B trial results for its drug, AOD9604, do not support the commercial viability of the drug as a
treatment for obesity. Development of the drug for this condition is terminated.
Trial results showed that weight loss compared to placebo at the primary and secondary endpoints of 12 or
24 weeks of treatment, was too low to reach statistical significance. The design of the obesity trial included
Phase 3 conditions, such as a broader population of subjects (536 in total) and a formal diet and exercise
programme. Under these additional conditions the AOD9604 treatment did not demonstrate the weight
loss required to support commercial outcomes.
The Company will focus on its other projects, including ACV1 for neuropathic pain (currently in Phase 2
trials) and AOD9604 for osteoporosis, as well as extending the application of its Oral Peptide Delivery
Platform to other high value drugs.
Dr Arthur Emmett, Chairman of Metabolic said “It is the nature of our industry that not all clinical stage
drugs progress from Phase 2 to Phase 3 trials. That is why the Board of Directors has long emphasised
the building of a strong and diverse pipeline. We will progress our programmes for the treatment of
neuropathic pain and osteoporosis, and are continuing with preclinical development of the Oral Peptide
Delivery Platform. These products are aimed at addressing unmet needs in multi-billion dollar markets”.
And, from another rediscovered download entitled "Australian Regulatory Guidelines for Biologicals
Part 3 - Access to unapproved biologicals, June 2011", and it goes something like this:
"Under the Therapeutic Goods Act 1989 (TG Act), biologicals can be used in a number of specific situations without the usual process of evaluation and approval for inclusion on the Australian Register of Therapeutic Goods (ARTG). These exempt uses include:
•specific exemptions:
–Special Access Scheme (SAS; such as for seriously ill patients)
–through an authorised prescriber (where authorised medical practitioners can authorise use of a particular exempt biological without previous approval from the Therapeutic Goods Administration [TGA])
–personal importation (where individuals can import a biological from overseas for their personal use, or for an immediate family member)
•special and experimental use (includes the Clinical Trial Notification and Clinical Trial Exemption schemes)."
Now, I reckon dash No 2 might have something to do with what the "dude" posted at Big Footy, about how they thought they could legimately use AOD. But, and this is the big "but", the very next page says this;
3.2Specific exemptions
3.2.1Special Access Scheme
The SAS allows an unapproved biological to be imported or supplied for a single patient, on a case-by-case basis.
For further information about the SAS, see the TGA website.
Two types of patients can benefit under the SAS:
•Category A patients are those who are seriously ill, those for whom death is likely to occur within months, or those who have a condition where premature death is likely if treatment is not provided.
•Category B patients are those who fall outside the definition of a Category A patient.
Consumers, medical practitioners and the TGA all have certain rights and responsibilities under the SAS:
•Rights of the patient include
–to have access to unapproved biologicals (e.g. for seriously ill patients), including biologicals that have been withdrawn from the Australian market for commercial or other reasons, biologicals provided to patients through a clinical trial while a marketing application is undergoing consideration, and biologicals available overseas but not marketed in Australia
–to give informed consent.
•Responsibilities of the medical practitioner (prescriber) include
–to classify patients as Category A or Category B
–to provide information about benefits and risks, and alternative treatments, and obtain informed consent from the patient
–to report adverse reactions.
•Responsibilities of the sponsor (supplier) include
–to provide six-monthly reports
–to monitor safety and use
–to report adverse reactions.
•Responsibilities of the TGA include
–to determine SAS requests
–to encourage the use of approved biologicals.
For further information about the rights and responsibilities under the SAS, see the TGA website.
Arrangements for supply for Category A and Category B patients
If the biological is available from a supplier in Australia, the TGA recommends that the medical practitioner or authorised prescriber (see below) contacts the sponsor to arrange supply. The supplier will require authorisation to lawfully release the biological.
If a biological is not available from an Australian sponsor, the prescriber must find an overseas source and arrange importation.
Category A
Supply of a therapeutic good for Category A patients requires notification of the TGA within 28 days of supply. To prescribe an unapproved biological for a category A patient, the medical practitioner must submit a completed Category A form Special Access Scheme to the sponsor and a copy to the TGA within 28 days, for notification purposes.
The Category A Form is available on the TGA website
Category B
SAS supply for a Category B patient requires prior approval by the TGA. Applications must be made to the TGA using the Special Access Scheme (SAS) request for Category B patients.
The Category B Form is available on the TGA website
The medical practitioner needs to seek the approval of a ‘delegate’ authorised under the TG Act. This can either be a delegated medical officer within the TGA or a medical practitioner outside the TGA (e.g. in a hospital). For Category B patients, a letter from the TGA with the issued approval number will be sent to the requesting doctor. Generally, a decision will be made within two working days.
A written consent form is needed for biologicals as part of all Category B applications.
The consent form is available on the TGA website
Applications to delegated medical officers within the TGA need to be made by fax or in writing.
External delegates are based within some hospitals and are authorised to approve a small number of therapeutic goods. Medical practitioners first need to submit an inquiry in writing to a hospital’s medical superintendent or chief pharmacist to determine whether a particular hospital has a local delegate.
Medical practitioners must provide the delegate with information about the patient, biological and prescriber, to use in deciding whether to approve supply to a Category B patient.
Table 3.1 summarises the information that the TGA requires to process applications for Category B patients under the SAS.
Table 3.1 Information required by the TGA for applications involving Category B patients
The patient
Patient detailsInitials, date of birth (or age), sex, patient ID or unit record number (if applicable), diagnosis, previous approval numbers for that patient (if applicable).
Clinical justificationAn outline of the seriousness of the patient’s condition, details of past treatment and, if other approved treatments are available, justification for the use of the unapproved biological in preference to those treatments.
The biological
Product detailsProduct description.
Administration and monitoring regimeDosage, route of administration, duration of treatment, details of proposed monitoring.
Efficacy and safety dataEfficacy and safety data sufficient to support the proposed use of the biological. A copy of the reference articles from which the data have been obtained should be included.
The prescriber
DetailsName, postal address, phone number, fax number.
Reporting adverse events
Under the SAS, the treating medical practitioner is responsible for reporting to the TGA any adverse reactions associated with the use of an unapproved biological.
Sponsors should also report to the TGA all serious and unexpected adverse reactions of which they have been informed, especially those that affect the risk–benefit assessment, and any information that may lead to changes in the use of the product. Fatal and life-threatening outcomes should be reported within seven calendar days of first knowledge, and followed up with a more comprehensive report within eight days of submitting the initial report.
For further information about reporting adverse reactions, see the TGA website
3.2.2Authorised prescribers
An authorised prescriber is a medical practitioner whom the TGA has granted authority to prescribe a specific unapproved biological to specified patients, or classes of patients (identified by their medical condition).
For further information about authorised prescribers, see the TGA website.
Once they become an authorised prescriber, the medical practitioner can prescribe that biological for the particular condition (‘indication’) to individual patients in their immediate care, without further approval from the TGA. Authorised prescribers can only supply the particular biological directly to the specified patient. They cannot supply the biological to other medical practitioners.
Medical practitioners who wish to become authorised prescribers must be endorsed by an ethics committee (e.g. the ethics committee of the hospital in which they practise, or any other appropriate ethics committee). Medical practitioners who do not have access to an ethics committee may be endorsed by an appropriate specialist college.
The rights and responsibilities of the patient, the authorised prescriber, the TGA and the sponsor are the same as described in Section 3.2.1 for the Special Access Scheme
Releasing information
The TGA will treat any information that it receives on the use of unapproved biologicals as confidential. Under the Freedom of Information Act 1982, consultation must occur between the TGA and the owners of the information before the documentation can be released. In addition, the Privacy Act 1988 limits the disclosure of personal information by parties in possession or control of records.
3.2.3Personal importation
Personal importation occurs when:
•an individual either brings a biological into Australia on their person or arranges from within Australia for a biological to be sent to them from an overseas supplier
and
•the biological is to be used by that individual or a member of their immediate family, and not sold or supplied to any other person.
Under these arrangements, personal importers need two permissions: permission to import, and permission to supply in Australia.
For further information about personal importation, see the TGA website
Quarantine clearance must be obtained before any material of biological origin (human, animal, plant or bacterial) is imported. The importer should contact the Australian Quarantine and Inspection Service (AQIS) to see whether an import permit is required.
Importation of biologicals under this scheme is also subject to a number of conditions and responsibilities.
Responsibility of the personal importer
People wishing to import unapproved biologicals for their personal use should be aware that, in many cases, the quality, safety and efficacy of the goods may be unknown. Therefore, they must be prepared to accept any risks associated with the use of such products. If an individual suffers adverse consequences from using such biologicals, information about the goods and redress may be difficult to obtain. The quantity imported cannot exceed 3 months’ supply per importation, and the total quantity imported each year cannot exceed 15 months’ supply at the manufacturer’s recommended maximum dosage. Individuals cannot import:
•injections that contain substances of human or animal origin (except insulin) without an SAS approval
•medical devices using tissues, cells or substances of animal origin (nonviable), or bacterial or recombinant origin
•products incorporating or intending to incorporate derivatives of human blood or blood plasma.
These products represent a high risk and approvals will only be given to the supervising physician by the TGA.
3.3Clinical trials
Access to biologicals for use in clinical trials can fall under one of two schemes:
•Clinical Trial Notification Scheme (CTN)
•Clinical Trial Exemption Scheme (CTX).
The schemes apply to the testing of any biologicals not entered on the ARTG, including any new preparations or uses, as well as use of an included biological in a clinical trial beyond the conditions of its marketing approval. The clinical trial arrangements (for both schemes) are based on the same risk-management principles that apply to medicines and medical devices (but with particular arrangements for higher risk biologicals). Special arrangements apply to clinical trials that are already under way.
All trials run under the CTN and CTX schemes must have an Australian sponsor.
Clinical trial sponsor
The sponsor is that person (e.g. medical practitioner), body, organisation (e.g. pharmaceutical company) or institution (e.g. hospital) that takes overall responsibility for running the trial, and signs either the Clinical Trial Notification Scheme form or the Clinical Trial Exemption Scheme form.
The sponsor usually initiates, organises and supports a clinical trial, and carries the medicolegal responsibility associated with running the trial. The responsibilities of sponsors are outlined in Section 5 of the CPMP/ICH Note for guidance on good clinical practice (CPMP/ICH/135/95), which is available on the TGA website. Sponsors must also comply with state and territory legislation.
A clinical trial of a biological could be either CTN or CTX.
The CTX Scheme is mandatory for a trial of any Class 4 biological unless:
•Use of the biological is supported by evidence from previous clinical use; or
•Has received clinical trial approval for an equivalent indication from a national regulatory body with comparable regulatory requirements.
The sponsor is responsible for initially deciding whether a trial should be run under a CTN or CTX scheme. They forward their application to the relevant human research ethics committee (HREC) who reviews the protocol, including the suggested scheme classification. If the HREC supports the current protocol and classification, the HREC provides advice to the ‘approving authority’, which decides whether the trial should be run. Alternatively, the HREC may recommend the trial be run under the alternative scheme.
3.3.1Clinical Trial Notification Scheme
The CTN Scheme allows access to unapproved therapeutic goods in special circumstances, without the need for prior approval from the TGA. Under the CTN Scheme, researchers submit all information on the proposed trial to their relevant HREC at the request of the sponsor. The HREC is responsible for assessing the scientific validity of the trial design, the safety and efficacy of the biological, the ethical acceptability of the trial process and finally approving the trial protocol. The institution where the trial will be conducted gives the final approval for conducting the trial at the site, taking into account the advice from the HREC. CTN Scheme trials cannot begin until the TGA has been notified (using the Notification of intent to supply unapproved therapeutic goods under the Clinical Trial Notification [CTN] Scheme form), and the appropriate notification fee has been paid (see Table 3.2). A new CTN form must be completed when there is a substantial change in the protocol, leading to a change in the HREC approval or the addition of new, unapproved biologicals to the trial.
At the end of the trial, a CTN clinical trial completion advice form must be completed and submitted to the TGA.
Further information about the CTN Scheme and the CTN application and completion forms are available on the TGA website.
3.3.2Clinical Trial Exemption Scheme
The CTX Scheme provides access to unapproved therapeutic goods after the TGA has assessed relevant data and approved the use of the biological for clinical trials.
The CTX Scheme is mandatory for clinical trials that use Class 4 biologicals (i.e. those that have the highest risks), unless the criteria noted in 3.3 above are met. The sponsor must submit an application for a clinical trial to the TGA for evaluation. The TGA delegate (either internal or external) decides whether the application is acceptable. If not, the trial cannot proceed until the sponsor has addressed the objection to the delegate’s satisfaction. Under the CTX Scheme, sponsors cannot begin a clinical trial until they have received written advice from the TGA about their application, approval from their relevant HREC and approval from the institution in which the trial will be run.
Sponsors must submit two separate forms to the TGA, the formal CTX Scheme application (Supply of unapproved therapeutic goods under the clinical trial exemption (CTX) scheme - Part 1 The CTX application) and the form that notifies the TGA of each new trial commencement. The former must be accompanied by the evaluation fee (see Table 3.2); the latter must be submitted within 28 days of the trial starting and there is no further fee.
At the end of the trial, a CTN or CTX Clinical Trial Completion Advice Form must be completed and submitted to the TGA."
They duck, they dodge, and they struggle to stand upright. Such is the way of these things.
Statistics: Posted by The OtherThommo — Sat 28 Mar 2015 2:31am