Wednesday, 9 February 2011

New version of EudraGMP allows access to information from all Member States

EudraGMP is the name for the Community database on manufacturing and import authorisations and Good Manufacturing Practice (GMP) certificates.

The European Medicines Agency has launched a new version of its EudraGMP database giving the general public access to information on manufacturing inspections performed by regulatory authorities from all European Economic Area (EEA) countries.

EudraGMP, which was first launched in May 2007, contains information on all manufacturers of human and veterinary medicines located in the EEA, and other manufacturers outside the EEA that have been inspected by European regulatory authorities. It includes details of the manufacturers' manufacturing and importation authorisations and good-manufacturing-practice (GMP) certificates.

The latest version of the database allows public access to the authorisation and GMP certificates coming from all countries in the EEA, including all European Union (EU) Member States plus Iceland, Liechtenstein and Norway. Previously, limited information coming from only some European countries was available to the public.

This initiative, which is part of the Agency's drive towards a greater level of openness and transparency, will
Improve the sharing of information between regulators and industry
Aid the co-ordination of activities related to manufacturing authorisations and GMP certificates between regulatory agencies in different European countries
Eliminate the need for industry to submit applications in paper form
Facilitate the sharing of information on the outcome of inspections in the EU with regulatory authorities elsewhere in the world.

The information in the database is continually updated by European regulatory authorities. The Agency expects around 3,000 new certificates to be imported into EudraGMP every year. It also expects the database to grow rapidly over the next few years, following the introduction of inspections in countries outside the EU and new GMP requirements for active gold

Tuesday, 18 January 2011

Questionable research removed from record as Lancet retracts publication

The British Medical Journal (BMJ) this month (January 5th) has published an article (the first of a special series) in which it outlines how a link between the measles, mumps & rubella vaccine and autism was artificially manufactured. A startling recap of how 'bogus data' has had an impact in the global perspective on vaccines and autism.

The article, by Brian Deer, a journalist, is titled "How the case against the MMR vaccine was fixed."

In 1998, Dr. Andrew Wakefield in the Lancet published his findings, based upon data from 12 patients, that there was an apparent link between the measles, mumps & rubella vaccine and the onset of behavioral symptoms.

In the decade following this publication, many parents decided not to vaccinate their children. It doesn't stretch the imagination that as a result, probably a number of children attracted the diseases unnecessarily, with who knows what results.

Flawed data, fabricated conclusions, severe allegations made against Dr. Wakefield. His original article in the Lancet was retracted by the Lancet February 2010, 12 years after the publication.

Of course, this is not the first time that fixed data is published, and it's likely not the last time. This case is so remarkable though, as it impacts the lives of so many children. Both from the side of unnecessarily worried parents making the choice not to vaccinate, but let's certainly not forget the parents of children with autism, desperately looking for a cause, something to blame, as is only natural. In this case, their position was openly and loudly pleaded by celebrity parents like Jenny McCarthy, who incidentally still supports the findings of Dr. Wakefield. Although it is somewhat understandable that someone does not want to let go of something to blame for such an unfair ordeal, I'm afraid it does more harm than good.

Perhaps needless to say, Dr. Wakefield also denies all allegations and stands by his findings.

However, currently 10 of the 12 original authors of the 1998 publication have retracted their support of the original study and its interpretation, the Lancet partially retracted in 2004 and after The General Medical Council ruled he had acted “dishonestly and irresponsibly” in doing his research, the Lancet completely retracted the article.

And therewith, they removed this questionable research and its conclusions from the records. With public voices still defending the discredited research, I doubt it will be the last we hear from it gold

Monday, 10 January 2011

FDA Basics for Industry

Over the last week, the FDA launched a new section of their website, called 'FDA Basics for Industry'.

"The website includes basic information about the regulatory process, including information that is frequently requested by industry."

The intention of the FDA is to improve communication between FDA and industry. The website contains information about the regulatory process, about current guidelines, about registrations, etc. It also includes a frequently asked questions section.

It looks like a good initiative, and a site that hopefully will continue to grow. It of course still aims at all areas covered by the FDA, including cosmetics, food and tobacco products.

The FDA reports that the starting of this website is a part of the agency's transparency initiative, launched in 2009 in response to President Obama’s commitment to openness in government.

I'm curious to find out if you find it a useful site, please feel free to gold

Monday, 3 January 2011

A True Investigator Meeting

Today I would like to draw your attention to a thought provoking column in the December issue of The Monitor, the publication of the Association of Clinical Research Professionals (ACRP). Dr. Joel S. Ross, MD, entitled his column "Investigating Investigator Meetings" (Page 84-85).

For members of the ACRP, you can read the article online here.

Dr. Ross in his column puts some critical notes to "practically invisible PIs" at investigator meetings. PIs who "blend into the furniture in the conference room", and asks out loud how they "reach the point of being so poorly prepared for the investigator meeting". He continues outlining how a "true PI" would prepare, versus the "practically invisible PI".

Rather than what his title suggests, the column is more about how a PI should prepare to be ready to start prescreening, screening and randomising eligible subjects than about investigator meetings. Although the link from this to investigator meetings is not made in so many words in his conclusion, Dr. Ross kind of makes the assertion that preparation for the one, should prepare a "true PI" for the other.

In this blog, I would like to add my perspective to his subtitle "With apologies to Shakespeare, 'To attend, or not to attend, meetings with the sponsor: That is the question'", addressing this from the angle of the sponsor.

Because indeed, the question 'to attend or not to attend' investigator meetings is a common question in clinical research. Where Dr. Ross makes the argument that if you attend, you should be well prepared to add benefit to the meeting, there is also a good argument to make for sponsors to make the investigator meetings more appealing to attend.

And here I don't mean by holding those meetings in exotic locations or providing an interesting evening (social) programme, though I can certainly appreciate the importance of providing opportunity for the participants to less formally discuss the trial other topics.

What I'm asserting is that sponsor companies often fail to cash in on the enormous potential that an investigator meeting has. Where the common purpose of an investigator meeting is to educate participants on the protocol and procedures, to provide a platform for discussion about the protocol, as well as to motivate all site staff present to commit to the trial at hand, the common format is commonly all but educational and certainly not motivational.

The average investigator meeting is a parade of presentations, one-way communications, where a conference room is often darkened to allow for better visual presentations and better naps. The organisation of an investigator meeting is often assigened to members of the clinical team who are already working overtime to start up the trial They get the organisation of the meeting as an added bonus. Presenters are often the subject matter experts (SMEs), who are, with all due respect, often not the best presenters. This does not do justice to the meeting, nor does it demonstrate respect for the time investment made the participants.

A True IM (Investigator Meeting) is set up with in mind the audience. It covers the topics knowing that the target audience is site staff and thus approaches it from their perspective, actively demonstrating how this is important for them. How the information applies to their job and answering the imagined questions the audience could have, before giving them the floor to come with further questions. It should not contain information the sponsor wants to share, but information the audience needs to know. The SMEs don't have to do the presenting, if they're not captivating presenters. As long as they're present for the best answers to challenging questions, a good presenter will be able to draw those questions by getting the audience interested.

Yes, investigators should come well prepared and ready to ask good questions, just as much as the sponsor should run the meeting well prepared, inviting, if not challenging the audience to come with good questions.

So, in the spirit of Dr. Ross' column about the "True PI", some points for a "True IM".

A True IM is interesting
A True IM is interactive
A True IM has two-way communication
A True IM has practical sessions
A True IM captivates the audience
A True IM involves the audience
A True IM is a platform for discsussion
A True IM has the lights on all day (in the room and in the eyes)
A True IM has proper follow up, including a Q&A from the meeting
A True IM respects all attending

Most of all:
A True IM is educational
A True IM is motivational wow gold

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

Tuesday, 8 December 2009

EMEA and FDA strengthen collaboration on inspections

The FDA (US) and the EMEA (EU) have started a Bilateral GCP Initiative as of September 1st, 2009. This program has been enabled by confidentiality arrangements between the EU and the FDA which deals with GCP-related information contained in applications for scientific advice, orphan medicines designation, pediatric investigational plans and marketing authorisation or postauthorisation activities of significant public health interest.

The intention of this Joint Inspection Program is that it will help to protect clinical trial subjects in the growing globalisation of clinical research. Most of the time, the same trials are used for Marketing Authorisation Applications (MAA) both in the US and in the EU. This initiative intents to ensure that those trials are executed uniformly, appropriately and ethically.

It concerns a pilot phase of 18 months, after which a joint assessment will lead to modifications and amendments to the scope and process, as needed.

The key objectives are:
 - To conduct periodic information exchanges on GCP-related information
 - To conduct collaborative GCP inspections
 - To share information on interpretation of GCP

The two regulators are currently inviting companies who are planning to submit applications fairly simultaneously to both regulatory authorities between September 2009 and September 2010, to volunteer to partner in this pilot. wow gold