Monday, 27 December 2010

1572 in International Setting

There has been ample discussion on the FDA1572 and its use in international research. The FDA has provided some useful guidance this year. Some highlights from that today.

Local Law vs CFR
If a foreign clinical study is being conducted under an IND, investigators are responsible for complying with the applicable laws and regulations of the country in which the study is being conducted, regardless of whether the study is being conducted under an IND. The FDA recommends that sponsors obtain signed, written statements from investigators acknowledging their commitment to comply with local laws and requirements. In addition, if a foreign clinical study is being conducted under an IND, the investigator must sign Form FDA 1572 (investigator statement) and ensure that the study is conducted in accordance with the investigator statement and all other applicable regulations under 21 CFR Part 312.

Signing of the 1572 by a foreign investigator in a study under IND
We know that a foreign investigators cannot commit to all of the requirements on the form, specifically IRB membership (21 CFR 56.107). IRB review and approval is required before a clinical study can be initiated under an IND (21 CFR 56.103(a)).

FDA may waive any of the IRB requirements but only when alternative mechanisms for ensuring protection of the rights and welfare of human subjects are acceptable. In this case, typically an Independent Ethics Committee (IEC) that operates in accordance with Good Clinical Practice (GCP) is utilized instead of a U.S. IRB. Although its membership and functions for assuring human subject protection are comparable to an IRB, an IEC may not meet all of the IRB requirements contained in 21 CFR Part 56.

The sponsor should submit a waiver request to the IND under which the study will be conducted. The sponsor will be informed by the agency in writing whether the waiver request is denied or granted.

IMPORTANT: If a waiver is granted, the sponsor should have investigators attach a copy of the letter granting the waiver to the signed 1572 in the investigator’s gold

Thursday, 3 June 2010

The FDA and the Declaration of Helsinki

It's not new, however awareness of the following is not yet all that wide-spread...
The FDA has abandoned the Declaration of Helsinki
After years of a power struggle between the American law makers and the World Medical Association (WMA), in 2008 the US Food and Drug Administration (FDA) took the drastic step of removing references to the Declaration of Helsinki from their documents. In April 2008, the FDA published a regulatory change ending the need for clinical trials conducted outside of the US to comply with the Declaration of Helsinki, for them to accept the data from those trials.
When the WMA published the fourth revision of the Declaration (1996), the FDA chose the side of the pharmaceutical industry, and fought the addition to the 1996 Declaration which intended to limit the use of placebos in clinical research where proven interventions had become established
In the Declaration of Helsinki 2000, the WMA states that investigational products "be tested against those of the best current prophylactic, diagnostic, and therapeutic methods." They continue to say that "this does not exclude the use of placebo, or no treatment, in studies where no proven prophylactic, diagnostic or therapeutic method exists."
The FDA preferred the 1989 version and publicly criticized the Declaration. Indirectly, they gained support from the EU regulators, who in their 2001 Clinical Trial Directive (2001/20/EC)  AND in their 2005 GCP Directive (2005/28/EC) refer to the 1996 version of the Declaration of Helsinki, blatantly ignoring the 2000 version and the 2002/2004 notes of clarification.
In 2006 the FDA pre-announced their intention to remove all references to the Declaration of Helsinki from their regulations. The WMA published their sixth (2008) revision on October 18, 2008, not budging to the pressure of the FDA, who published the Final Rule in April 2008 . The Final Rule became effective October 27, 2008:

"The final rule replaces the requirement that [non-IND foreign clinical studies] be conducted in accordance with ethical principles stated in the Declaration of Helsinki (Declaration) issued by the World Medical Association (WMA), specifically the 1989 version (1989 Declaration), with a requirement that the studies be conducted in accordance with good clinical practice (GCP), including review and approval by an independent ethics committee (IEC). The final rule updates the standards for the acceptance of foreign clinical studies not conducted under an IND and helps ensure the protection of human subjects and the quality and integrity of data obtained from these studies."
The use of placebo groups overseas is justified by arguing that patients in poorer countries would not have access to existing standard treatments outside of the trial. The trial simply compares a new treatment against the existing “standard of care” in the country where the trial is conducted. The result however is that a study that is considered unethical in the US, IS allowed to be run in another country.
You can argue that a country is allowed to set higher than the internationally accepted minimal standards for within its own territory. This, however, is a situation where a country is taking the more and more accepted international standards, and decides that as far as they are concerned, data derived from clinical trials that do not live up to those international standards, is now acceptable to them.
Pharmaceutical companies have responded generally positive to the FDA's change in point of view, some even with immediate effectiveness removing the Declaration of Helsinki from their protocols.
There are generally two advantages for the pharmaceutical company for doing placebo controlled trials.
  • It is easier to show that a drug is better than placebo than existing therapies. Active comparator trials require more patients and consequently more time and money.
  • If the existing treatment turns out to be more efficacious, it enforces the market position of the competitors product.
We should be cautious, however, to take the word of the FDA as gospel for the rest of the world. Just because the FDA is saying that they accept foreign clinical studies even if they do not adhere to the Declaration of Helsinki, does that mean we should all collectively abandon the Declaration? Do we, each, not have the personal and individual responsibility to never let there be any doubt about the ethical standards we apply to our research involving human subjects?
Participants in a trial are providing a valuable service to the investigators and the industry. This has always implied a special requirement that the investigator protect the interests of the subjects.
The FDA's change in what they accept from the rest of the world does not automatically have to change what the rest of the world offers to the gold