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TERMS OF USE AGREEMENT AND PRIVACY POLICY
Use of this site is governed by our Terms of Use Agreement and Privacy Policy.
TERMS OF USE AGREEMENT
Welcome to this Web site. By using this site, you are agreeing to comply with and be bound by the following terms of use. PLEASE REVIEW THE FOLLOWING TERMS CAREFULLY, BECAUSE THERE ARE SOME NASTY SURPRISES. If you do not agree to these terms, you should not use this site. Just go away and don’t come back. The term “Dr. Peter Rost,” “us,” “we” or “our” refers to Dr. Peter Rost. The term “you” refers to you, the user or viewer of our Web site. Duh.
Acceptance of Agreement.
You agree to the terms and conditions set forth in this Terms of Use Agreement (“Agreement”) with respect to our site (the “Site”). This Agreement constitutes the entire and only agreement between us and you and also incorporates the separate, very humorous legal disclaimer by reference which can be found here: http://peterrost.blogspot.com/2006/05/important-legal-disclaimer.html. This agreement supersedes all prior or contemporaneous agreements, representations, warranties and understandings with respect to the Site and the subject matter of this Agreement. This Agreement may be amended at any time by us from time to time without specific notice to you and is effective retroactively from the beginning of time, when God created Earth. The latest version of the Agreement will be posted on this Site, and you should review this Agreement prior to using the Site. If you don’t, you are a lazy bastard and you can’t complain.
Copyright.
The content, organization, graphics, design, compilation, magnetic translation, digital conversion and other matters related to the Site are protected under applicable copyrights, trademarks and other proprietary (including but not limited to intellectual property) rights. The copying, redistribution, use or publication by you of any such matters or any part of the Site, except as allowed by "Limited License," below, is strictly prohibited. If you do so without a license, you hereby agree to pay us a one time fee of $1,000,000 ($1 Million), payable within ten days. You do not acquire ownership rights to any article, document or other materials viewed through the Site. The posting of information or materials on the Site does not constitute a waiver of any right in such information and materials. Some of the content on the Site may be the copyrighted work of third parties.
Limited License; Permitted Uses.
You are granted a non-exclusive, non-transferable, revocable license (a) to access and use the Site solely in accordance with this Agreement; (b) to use the Site solely for internal, personal, non-commercial and non-legal purposes; and (c) to print out or save on your computer discrete information from this Site solely for internal, personal, non-commercial and non-legal purposes provided that you maintain all copyright and other policies contained therein; and (d) to use part or entire posts from this Site on your Site, provided you include a link back to the original post. No print out or electronic version of any part of the Site or its contents may be used by you in any litigation or arbitration matter whatsoever under any circumstances. If you violate this provision, i.e., you print out a post and later use this in Court or for any legal purposes whatsoever, you hereby agree to pay us a one time fee of $1,000,000 ($1 Million). If the firm you work for refuses to pay, you will be personally liable for this amount. You don’t like it? Fine, don’t come here and abuse the content of this blog.
Restrictions and Prohibitions on Use.
Your license for access and use of the Site and any information, materials or documents (collectively defined as “Content and Materials”) therein are subject to the following restrictions and prohibitions on use: You may not (a) copy, print, save (except for the express limited purpose permitted above), republish, display, distribute, transmit, sell, rent, lease, loan or otherwise make available in any form or by any means all or any portion of the Site or any Content and Materials retrieved therefrom; (b) use the Site or any materials obtained from the Site to develop, of as a component of, any information, storage and retrieval system, database, information base, or similar resource (in any media now existing or hereafter developed), that is offered for commercial distribution of any kind, including through sale, license, lease, rental, subscription, or any other commercial distribution mechanism; (c) create compilations or derivative works of any Content and Materials from the Site except as described above; (d) use any Content and Materials from the Site in any manner that may infringe any copyright, intellectual property right, proprietary right, or property right of us or any third parties; (e) remove, change or obscure any copyright notice or other proprietary notice or terms of use contained in the Site; (f) make any portion of the Site available through any timesharing system, service bureau, the Internet or any other technology now existing or developed in the future; (g) remove, decompile, disassemble or reverse engineer any Site software or use any network monitoring or discovery software to determine the Site architecture; (h) use any automatic or manual process to harvest information from the Site; (i) use the Site for the purpose of gathering information for or transmitting (1) unsolicited commercial e-mail; (2) e-mail that makes use of headers, invalid or nonexistent domain names, or other means of deceptive addressing; and (3) unsolicited telephone calls or facsimile transmissions; (j) use the Site in a manner that violates any state or federal law regulating e-mail, facsimile transmissions or telephone solicitations; and (k) export or re-export the Site or any portion thereof, or any software available on or through the Site, in violation of the export control laws or regulations of the United States.
No Legal Advice.
Information contained on or made available through the Site is not intended to and does not constitute legal advice, recommendations, mediation or counseling under any circumstance. Dr. Peter Rost is not a lawyer. We do not warrant or guarantee the accurateness, completeness, adequacy or currency of the information contained in or linked to the Site. Your use of information on the Site or materials linked to the Site is entirely at your own risk. You should not act or rely on any information on the Site without seeking the advice of a competent attorney licensed to practice in your jurisdiction for your particular problem. The information contained herein does not necessarily reflect the opinions of Dr. Rost.
Forms, Agreements & Documents
We may make available through the Site music files, film files, various documents and legal documents (collectively, “Documents”). All Documents are provided on a non-exclusive license basis only for your personal one-time use for non-commercial purposes, without any right to re-license, sublicense, distribute, assign or transfer such license. Documents are provided without any representations or warranties, express or implied, as to their suitability, legal effect, completeness, currentness (is that a real word?), accuracy, and/or appropriateness. THE DOCUMENTS ARE PROVIDED “AS IS”, “AS AVAILABLE”, AND WITH “ALL FAULTS”, AND WE AND ANY PROVIDER OF THE DOCUMENTS DISCLAIM ANY WARRANTIES, INCLUDING BUT NOT LIMITED TO THE WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE. The Documents may be inappropriate for your particular circumstances. Furthermore, state laws may require different or additional provisions to ensure the desired result. You should consult with legal counsel to determine the appropriate legal or business documents necessary for your particular transactions, as the Documents may be fake, irrelevant, or downright stupid, and may not be applicable to a particular situation.
Linking to the Site.
You may provide links to the Site, provided (a) that you do not remove or obscure, by framing or otherwise, the copyright notice or other notices on the Site, (b) your site does not engage in illegal or pornographic activities, (you may show lightly dressed pretty women in non pornographic poses, a policy which we will interpret broadly) and (c) you discontinue providing links to the Site immediately upon request by us.
You may send us e-mail. However, you should not send us confidential or sensitive information via e-mail because your communication will not be treated as privileged or confidential and it may be published on this site. You should also note that the security of Internet e-mail is uncertain. By sending sensitive or confidential e-mail messages which are not encrypted, you accept the risks of such uncertainty and possible lack of confidentiality over the Internet.
Errors, Corrections and Changes.
We do not represent or warrant that the Site will be error-free, free of viruses or other harmful components, or that defects will be corrected. If we can find a cookie which takes a picture of you looking at your screen, we reserve the right to use that cookie. Or eat it. We do not represent or warrant that the information available on or through the Site will be correct, accurate, timely or otherwise reliable. The law is constantly changing and the information may not be complete or accurate. And we don’t know the law because we are not lawyers. Each legal issue depends on its individual facts and different jurisdictions have different laws and regulations. Dr. Rost is not a lawyer (did we say that already?) and sometimes has no idea what he is talking about, other times he knows very well. That's for you to figure out and you use this site at your own risk. We may make changes to the features, functionality or content of the Site at any time. We reserve the right in our sole discretion to edit or delete any documents, information or other content appearing on the Site.
Third Party Content.
Third party content may appear on the Site or may be accessible via links from the Site. We are not responsible for and assume no liability for any third party content. You understand that the information and opinions in the third party content represent solely the thoughts of someone and is neither endorsed by nor does it necessarily reflect our belief.
Unlawful Activity.
We reserve the right to investigate complaints or reported violations of this Agreement and to take any action we deem appropriate, including but not limited to reporting any suspected unlawful activity to law enforcement officials, regulators, or other third parties and disclosing any information necessary or appropriate to such persons or entities relating to your profile, e-mail addresses, usage history, IP addresses and traffic information. We reserve the right to do everything legally permissible to find out who you are and publicly welcome you as a reader or mock you if we don't like your visit.
Indemnification.
You agree to indemnify, defend and hold us and our partners, associates, agents, attorneys, employees, subcontractors, successors, assigns, and affiliates (collectively, “Affiliated Parties”) harmless from any liability, loss, claim and expense related to your violation of this Agreement or use of the Site.
Disclaimer.
THE INFORMATION, CONTENT AND DOCUMENTS FROM OR THROUGH THE SITE ARE PROVIDED “AS-IS,” “AS AVAILABLE,” WITH “ALL FAULTS”, AND ALL WARRANTIES, EXPRESS OR IMPLIED, ARE DISCLAIMED (INCLUDING BUT NOT LIMITED TO THE DISCLAIMER OF ANY IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE). THE INFORMATION AND SITE MAY CONTAIN BUGS, ERRORS, PROBLEMS OR OTHER LIMITATIONS. IT MAY EVEN MAKE YOUR COMPUER EXPLODE, BUT WE DON’T THINK IT WILL. WE AND OUR AFFILIATED PARTIES HAVE NO LIABILITY WHATSOEVER, EXCEPT AS PROVIDED in one of the sections above, we don't remember which one. IN PARTICULAR, BUT NOT AS A LIMITATION THEREOF, WE AND OUR AFFILIATED PARTIES ARE NOT LIABLE FOR ANY INDIRECT, SPECIAL, INCIDENTAL OR CONSEQUENTIAL DAMAGES (INCLUDING DAMAGES FOR LOSS OF BUSINESS, LOSS OF PROFITS, LITIGATION, OR THE LIKE), WHETHER BASED ON BREACH OF CONTRACT, BREACH OF WARRANTY, TORT (INCLUDING NEGLIGENCE), PRODUCT LIABILITY OR OTHERWISE, EVEN IF ADVISED OF THE POSSIBILITY OF SUCH DAMAGES. THE NEGATION AND LIMITATION OF DAMAGES SET FORTH ABOVE ARE FUNDAMENTAL ELEMENTS OF THE BASIS OF THE BARGAIN BETWEEN US AND YOU. THIS SITE AND THE INFORMATION PRESENTED WOULD NOT BE PROVIDED WITHOUT SUCH LIMITATIONS. NO ADVICE OR INFORMATION, WHETHER ORAL OR WRITTEN, OBTAINED BY YOU FROM US THROUGH THE SITE OR OTHERWISE SHALL CREATE ANY WARRANTY, REPRESENTATION OR GUARANTEE NOT EXPRESSLY STATED IN THIS AGREEMENT.
ALL RESPONSIBILITY OR LIABILITY FOR ANY DAMAGES CAUSED BY VIRUSES CONTAINED WITHIN THE ELECTRONIC FILE CONTAINING A FORM OR DOCUMENT IS DISCLAIMED.
Limitation of Liability
(a) We and any Affiliated Party shall not be liable for any loss, injury, claim, liability, or damage of any kind resulting in any way from (i) any errors in or omissions from the Site or information obtained, (ii) the unavailability or interruption of the Site or any features thereof, (iii) your use of the Site, (iv) the content contained on the Site, or (v) any delay or failure in performance beyond the control of an Affiliated Party.
(b) THE AGGREGATE LIABILITY OF US AND THE AFFILIATED PARTIES IN CONNECTION WITH ANY CLAIM ARISING OUT OF OR RELATING TO THE SITE SHALL NOT EXCEED $10 AND THAT AMOUNT SHALL BE IN LIEU OF ALL OTHER REMEDIES WHICH YOU MAY HAVE AGAINST US AND ANY AFFILIATED PARTY. IF YOU DON’T LIKE THIS, DON’T COME HERE AND DON’T EMAIL US! IT’S ALL VERY SIMPLE.
Use of Information/Privacy Policy.
We reserve the right, and you authorize us, to the use and assignment of all information regarding Site uses by you and all information provided by you in any manner consistent with our Privacy Policy. Our Privacy Policy, as it may change from time to time, is a part of this Agreement. You may review this Privacy Policy below.
Links to other Web Sites.
The Site contains links to other Web sites. We are not responsible for the content, accuracy or opinions express in such Web sites, and such Web sites are not investigated, monitored or checked for accuracy or completeness by us. But they are probably really hot web sites and we recommend reading them. Inclusion of any linked Web site on our Site does not imply approval or endorsement of the linked Web site by us. If you decide to leave our Site and access these third-party sites, you do so at your own risk. If your computer explodes, please sue the battery manufacturer and not us.
Copyrights and Copyright Agents.
We respect the intellectual property of others, and we ask you to do the same. If you believe that your work has been copied in a way that constitutes copyright infringement, please provide us with the following information:
a. An electronic or physical signature of the person authorized to act on behalf of the owner of the copyright interest;
b. A description of the copyrighted work that you claim has been infringed;
c. A description of where the material that you claim is infringing is located on the Site;
d. Your address, telephone number, and e-mail address;
e. A statement by you that you have a good faith belief that the disputed use is not authorized by the copyright owner, its agent, or the law; and
f. A statement by you, made under penalty of perjury, that the above information in your Notice is accurate and that you are the copyright owner or authorized to act on the copyright owner’s behalf.
g. Scan all this information into a pdf document and email this to rostpeter (insert @)hotmail.com.
Legal Compliance.
You agree to comply with all applicable domestic and international laws, statutes, ordinances and regulations regarding your use of the Site and the Content and Materials provided therein.
Miscellaneous.
This Agreement shall be treated as though it were executed and performed in New Jersey, and shall be governed by and construed in accordance with the laws of the State of New Jersey (without regard to conflict of law principles). If you don't like that we can use Sweden instead. But only if we agree to do so. ANY CAUSE OF ACTION BY YOU WITH RESPECT TO THE SITE MUST BE INSTITUTED WITHIN ONE (1) MONTH AFTER THE CAUSE OF ACTION AROSE OR BE FOREVER WAIVED AND BARRED. All actions shall be subject to the limitations set forth above. The language in this Agreement shall be interpreted as to its fair meaning and not strictly for or against any party. THE FACT THAT WE USE HUMOR IN THIS DOCUMENT SHALL NOT BE HELD AGAINST US AND SHALL NOT DIMINISH THE IMPORTANCE OF THIS DOCUMENT. Any rule of construction to the effect that ambiguities are to be resolved against the drafting party shall not apply in interpreting this Agreement. The headings in this Agreement are included for convenience only and shall neither affect the construction or interpretation of any provision of this Agreement nor affect any of the rights or obligations of the parties to this Agreement. Should any part of this Agreement be held invalid or unenforceable, that portion shall be construed as much as possibly consistent with applicable law and the remaining portions shall remain in full force and effect. So if we don’t get $1,000,000 when you breach this agreement, we expect to receive $999,999, and so on. To the extent that anything in or associated with the Site is in conflict or inconsistent with this Agreement, this Agreement shall take precedence. Our failure to enforce any provision of this Agreement shall not be deemed a waiver of such provision nor of the right to enforce such provision. Our rights under this Agreement shall survive any termination of this Agreement.
PRIVACY POLICY
Thank you for visiting this cool web site. We are pleased to provide you this Privacy Policy to inform you of our practices with respect to the collection and use of information about visitors to our web site. By using this site, you consent to the following terms and our Terms of Use Agreement.
What Information Do We Collect?
Anything we can. When you visit our web site you may provide us with two types of information: personal information you knowingly choose to disclose that is collected on an individual basis and web site use information collected on an individual and aggregate basis as you and others browse our web site.
Personal Information You Choose to Provide
You may voluntarily provide us personally identifiable information. If you choose to correspond with us through e-mail, we may retain the content of your e-mail messages together with your e-mail address and our responses and we may publish, eat, or create anything we like based on this correspondence.
Similar to other web sites, our web site utilizes a standard technology called “cookies” (see explanation below, “What Are Cookies?”) and Web server logs to collect information about how our web site is used. Information gathered through cookies and Web server logs may include the date and time of visits, the pages viewed, time spent at our web site, and the web sites visited just before and just after our web site as well as other personal information that happens to get stuck.
How Do We Use the Information That You Provide to Us?
Broadly speaking, we use personal information for purposes of enhancing or modifying our site, administering and expanding our business activities or responding to inquiries. We also use it for fun, laugh our heads off, and to write posts.
What Are Cookies?
A cookie is a very small text document, which often includes an anonymous unique identifier. When you visit a web site, that site’s computer asks your computer for permission to store this file in a part of your hard drive specifically designated for cookies. You can disable this function, so if you didn't you have nothing to complain about. But if you do disable this function most web sites you like will not recognize you and you will probably enable the function again, because you are lazy. Each web site can send its own cookie to your browser if your browser’s preferences allow it, but (to protect your privacy) your browser only permits a web site to access the cookies it has already sent to you, not the cookies sent to you by other sites.
How Do We Use Information We Collect from Cookies?
In short, any way we want. As you use our web site, the site uses its cookies to differentiate you from other users. It can’t take your picture or check you shoe size, but you can assume that one day it will. Cookies, in conjunction with our Web server’s log files, allow us to calculate the aggregate number of people visiting our web site and which parts of the site are most popular. It also helps us identify crazy people who read this blog once every hour. This helps us gather feedback in order to constantly improve our web site. And to spy on the people who spy on us. Cookies do not allow us to gather any personal information about you, which is really sad, and we do not generally store any personal information that you provided to us in your cookies, but we may. Hey, so you never know.
Sharing Information with Third Parties
We generally do not share information collected with third parties but reserve the right to do so. And if someone offers us a gazillion dollars we may cave in and share anything.
How Do We Protect Your Information?
E-mail is not recognized as a secure medium of communication. You should not send private or confidential information to us by e-mail or otherwise in connection with our site. Anyway, anything you send we may publish or do whatever we want with.
Certain Disclosures
We may disclose your personal information if required to do so by law or subpoena or if we believe that such action is necessary to (a) conform to the law or comply with legal process served on us or parties affiliated with us; (b) protect and defend our rights and property, our Site, the users of our site, and/or our affiliated parties; and/or (c) act under circumstances to protect the safety of users of the site, us, or third parties.
What About Other web sites Linked to Our web site?
We love 'em. But we are not responsible for the practices employed by web sites linked to or from our web site nor the information or content contained therein. Often links to other web sites are provided solely as pointers to information on topics that may be useful to the users of our web site.
Please remember that when you use a link to go from our web site to another web site, our Privacy Policy is no longer in effect. Your browsing and interaction on any other web site, including web sites which have a link on our web site, is subject to that web site’s own rules and policies. Please read over those rules and policies before proceeding.
Questions and Updates
If you have any questions or suggestions about our privacy practices, or you wish to update or correct any personally identifiable information that you have chosen to provide us, please feel free to contact us at our email, which you will find somewhere on this blog.
Your Consent
By using our web site you consent to our collection and use of your personal information as described in this Privacy Policy. If you don't simply don't come back. That wasn't hard, was it? If we change our privacy policies and procedures, we will post those changes on our web site to keep you aware of what information we collect, how we use it and under what circumstances we may disclose it. Or maybe we will not, if we forget. But we will try.
TERMS OF USE AGREEMENT
Welcome to this Web site. By using this site, you are agreeing to comply with and be bound by the following terms of use. PLEASE REVIEW THE FOLLOWING TERMS CAREFULLY, BECAUSE THERE ARE SOME NASTY SURPRISES. If you do not agree to these terms, you should not use this site. Just go away and don’t come back. The term “Dr. Peter Rost,” “us,” “we” or “our” refers to Dr. Peter Rost. The term “you” refers to you, the user or viewer of our Web site. Duh.
Acceptance of Agreement.
You agree to the terms and conditions set forth in this Terms of Use Agreement (“Agreement”) with respect to our site (the “Site”). This Agreement constitutes the entire and only agreement between us and you and also incorporates the separate, very humorous legal disclaimer by reference which can be found here: http://peterrost.blogspot.com/2006/05/important-legal-disclaimer.html. This agreement supersedes all prior or contemporaneous agreements, representations, warranties and understandings with respect to the Site and the subject matter of this Agreement. This Agreement may be amended at any time by us from time to time without specific notice to you and is effective retroactively from the beginning of time, when God created Earth. The latest version of the Agreement will be posted on this Site, and you should review this Agreement prior to using the Site. If you don’t, you are a lazy bastard and you can’t complain.
Copyright.
The content, organization, graphics, design, compilation, magnetic translation, digital conversion and other matters related to the Site are protected under applicable copyrights, trademarks and other proprietary (including but not limited to intellectual property) rights. The copying, redistribution, use or publication by you of any such matters or any part of the Site, except as allowed by "Limited License," below, is strictly prohibited. If you do so without a license, you hereby agree to pay us a one time fee of $1,000,000 ($1 Million), payable within ten days. You do not acquire ownership rights to any article, document or other materials viewed through the Site. The posting of information or materials on the Site does not constitute a waiver of any right in such information and materials. Some of the content on the Site may be the copyrighted work of third parties.
Limited License; Permitted Uses.
You are granted a non-exclusive, non-transferable, revocable license (a) to access and use the Site solely in accordance with this Agreement; (b) to use the Site solely for internal, personal, non-commercial and non-legal purposes; and (c) to print out or save on your computer discrete information from this Site solely for internal, personal, non-commercial and non-legal purposes provided that you maintain all copyright and other policies contained therein; and (d) to use part or entire posts from this Site on your Site, provided you include a link back to the original post. No print out or electronic version of any part of the Site or its contents may be used by you in any litigation or arbitration matter whatsoever under any circumstances. If you violate this provision, i.e., you print out a post and later use this in Court or for any legal purposes whatsoever, you hereby agree to pay us a one time fee of $1,000,000 ($1 Million). If the firm you work for refuses to pay, you will be personally liable for this amount. You don’t like it? Fine, don’t come here and abuse the content of this blog.
Restrictions and Prohibitions on Use.
Your license for access and use of the Site and any information, materials or documents (collectively defined as “Content and Materials”) therein are subject to the following restrictions and prohibitions on use: You may not (a) copy, print, save (except for the express limited purpose permitted above), republish, display, distribute, transmit, sell, rent, lease, loan or otherwise make available in any form or by any means all or any portion of the Site or any Content and Materials retrieved therefrom; (b) use the Site or any materials obtained from the Site to develop, of as a component of, any information, storage and retrieval system, database, information base, or similar resource (in any media now existing or hereafter developed), that is offered for commercial distribution of any kind, including through sale, license, lease, rental, subscription, or any other commercial distribution mechanism; (c) create compilations or derivative works of any Content and Materials from the Site except as described above; (d) use any Content and Materials from the Site in any manner that may infringe any copyright, intellectual property right, proprietary right, or property right of us or any third parties; (e) remove, change or obscure any copyright notice or other proprietary notice or terms of use contained in the Site; (f) make any portion of the Site available through any timesharing system, service bureau, the Internet or any other technology now existing or developed in the future; (g) remove, decompile, disassemble or reverse engineer any Site software or use any network monitoring or discovery software to determine the Site architecture; (h) use any automatic or manual process to harvest information from the Site; (i) use the Site for the purpose of gathering information for or transmitting (1) unsolicited commercial e-mail; (2) e-mail that makes use of headers, invalid or nonexistent domain names, or other means of deceptive addressing; and (3) unsolicited telephone calls or facsimile transmissions; (j) use the Site in a manner that violates any state or federal law regulating e-mail, facsimile transmissions or telephone solicitations; and (k) export or re-export the Site or any portion thereof, or any software available on or through the Site, in violation of the export control laws or regulations of the United States.
No Legal Advice.
Information contained on or made available through the Site is not intended to and does not constitute legal advice, recommendations, mediation or counseling under any circumstance. Dr. Peter Rost is not a lawyer. We do not warrant or guarantee the accurateness, completeness, adequacy or currency of the information contained in or linked to the Site. Your use of information on the Site or materials linked to the Site is entirely at your own risk. You should not act or rely on any information on the Site without seeking the advice of a competent attorney licensed to practice in your jurisdiction for your particular problem. The information contained herein does not necessarily reflect the opinions of Dr. Rost.
Forms, Agreements & Documents
We may make available through the Site music files, film files, various documents and legal documents (collectively, “Documents”). All Documents are provided on a non-exclusive license basis only for your personal one-time use for non-commercial purposes, without any right to re-license, sublicense, distribute, assign or transfer such license. Documents are provided without any representations or warranties, express or implied, as to their suitability, legal effect, completeness, currentness (is that a real word?), accuracy, and/or appropriateness. THE DOCUMENTS ARE PROVIDED “AS IS”, “AS AVAILABLE”, AND WITH “ALL FAULTS”, AND WE AND ANY PROVIDER OF THE DOCUMENTS DISCLAIM ANY WARRANTIES, INCLUDING BUT NOT LIMITED TO THE WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE. The Documents may be inappropriate for your particular circumstances. Furthermore, state laws may require different or additional provisions to ensure the desired result. You should consult with legal counsel to determine the appropriate legal or business documents necessary for your particular transactions, as the Documents may be fake, irrelevant, or downright stupid, and may not be applicable to a particular situation.
Linking to the Site.
You may provide links to the Site, provided (a) that you do not remove or obscure, by framing or otherwise, the copyright notice or other notices on the Site, (b) your site does not engage in illegal or pornographic activities, (you may show lightly dressed pretty women in non pornographic poses, a policy which we will interpret broadly) and (c) you discontinue providing links to the Site immediately upon request by us.
You may send us e-mail. However, you should not send us confidential or sensitive information via e-mail because your communication will not be treated as privileged or confidential and it may be published on this site. You should also note that the security of Internet e-mail is uncertain. By sending sensitive or confidential e-mail messages which are not encrypted, you accept the risks of such uncertainty and possible lack of confidentiality over the Internet.
Errors, Corrections and Changes.
We do not represent or warrant that the Site will be error-free, free of viruses or other harmful components, or that defects will be corrected. If we can find a cookie which takes a picture of you looking at your screen, we reserve the right to use that cookie. Or eat it. We do not represent or warrant that the information available on or through the Site will be correct, accurate, timely or otherwise reliable. The law is constantly changing and the information may not be complete or accurate. And we don’t know the law because we are not lawyers. Each legal issue depends on its individual facts and different jurisdictions have different laws and regulations. Dr. Rost is not a lawyer (did we say that already?) and sometimes has no idea what he is talking about, other times he knows very well. That's for you to figure out and you use this site at your own risk. We may make changes to the features, functionality or content of the Site at any time. We reserve the right in our sole discretion to edit or delete any documents, information or other content appearing on the Site.
Third Party Content.
Third party content may appear on the Site or may be accessible via links from the Site. We are not responsible for and assume no liability for any third party content. You understand that the information and opinions in the third party content represent solely the thoughts of someone and is neither endorsed by nor does it necessarily reflect our belief.
Unlawful Activity.
We reserve the right to investigate complaints or reported violations of this Agreement and to take any action we deem appropriate, including but not limited to reporting any suspected unlawful activity to law enforcement officials, regulators, or other third parties and disclosing any information necessary or appropriate to such persons or entities relating to your profile, e-mail addresses, usage history, IP addresses and traffic information. We reserve the right to do everything legally permissible to find out who you are and publicly welcome you as a reader or mock you if we don't like your visit.
Indemnification.
You agree to indemnify, defend and hold us and our partners, associates, agents, attorneys, employees, subcontractors, successors, assigns, and affiliates (collectively, “Affiliated Parties”) harmless from any liability, loss, claim and expense related to your violation of this Agreement or use of the Site.
Disclaimer.
THE INFORMATION, CONTENT AND DOCUMENTS FROM OR THROUGH THE SITE ARE PROVIDED “AS-IS,” “AS AVAILABLE,” WITH “ALL FAULTS”, AND ALL WARRANTIES, EXPRESS OR IMPLIED, ARE DISCLAIMED (INCLUDING BUT NOT LIMITED TO THE DISCLAIMER OF ANY IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE). THE INFORMATION AND SITE MAY CONTAIN BUGS, ERRORS, PROBLEMS OR OTHER LIMITATIONS. IT MAY EVEN MAKE YOUR COMPUER EXPLODE, BUT WE DON’T THINK IT WILL. WE AND OUR AFFILIATED PARTIES HAVE NO LIABILITY WHATSOEVER, EXCEPT AS PROVIDED in one of the sections above, we don't remember which one. IN PARTICULAR, BUT NOT AS A LIMITATION THEREOF, WE AND OUR AFFILIATED PARTIES ARE NOT LIABLE FOR ANY INDIRECT, SPECIAL, INCIDENTAL OR CONSEQUENTIAL DAMAGES (INCLUDING DAMAGES FOR LOSS OF BUSINESS, LOSS OF PROFITS, LITIGATION, OR THE LIKE), WHETHER BASED ON BREACH OF CONTRACT, BREACH OF WARRANTY, TORT (INCLUDING NEGLIGENCE), PRODUCT LIABILITY OR OTHERWISE, EVEN IF ADVISED OF THE POSSIBILITY OF SUCH DAMAGES. THE NEGATION AND LIMITATION OF DAMAGES SET FORTH ABOVE ARE FUNDAMENTAL ELEMENTS OF THE BASIS OF THE BARGAIN BETWEEN US AND YOU. THIS SITE AND THE INFORMATION PRESENTED WOULD NOT BE PROVIDED WITHOUT SUCH LIMITATIONS. NO ADVICE OR INFORMATION, WHETHER ORAL OR WRITTEN, OBTAINED BY YOU FROM US THROUGH THE SITE OR OTHERWISE SHALL CREATE ANY WARRANTY, REPRESENTATION OR GUARANTEE NOT EXPRESSLY STATED IN THIS AGREEMENT.
ALL RESPONSIBILITY OR LIABILITY FOR ANY DAMAGES CAUSED BY VIRUSES CONTAINED WITHIN THE ELECTRONIC FILE CONTAINING A FORM OR DOCUMENT IS DISCLAIMED.
Limitation of Liability
(a) We and any Affiliated Party shall not be liable for any loss, injury, claim, liability, or damage of any kind resulting in any way from (i) any errors in or omissions from the Site or information obtained, (ii) the unavailability or interruption of the Site or any features thereof, (iii) your use of the Site, (iv) the content contained on the Site, or (v) any delay or failure in performance beyond the control of an Affiliated Party.
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Placebos Are Getting More Effective. Drugmakers Are Desperate to Know Why.
Wired Magazine
Merck was in trouble. In 2002, the pharmaceutical giant was falling behind its rivals in sales. Even worse, patents on five blockbuster drugs were about to expire, which would allow cheaper generics to flood the market. The company hadn't introduced a truly new product in three years, and its stock price was plummeting.In interviews with the press, Edward Scolnick, Merck's research director, laid out his battle plan to restore the firm to preeminence. Key to his strategy was expanding the company's reach into the antidepressant market, where Merck had lagged while competitors like Pfizer and GlaxoSmithKline created some of the best-selling drugs in the world. "To remain dominant in the future," he told Forbes, "we need to dominate the central nervous system."
His plan hinged on the success of an experimental antidepressant codenamed MK-869. Still in clinical trials, it looked like every pharma executive's dream: a new kind of medication that exploited brain chemistry in innovative ways to promote feelings of well-being. The drug tested brilliantly early on, with minimal side effects, and Merck touted its game-changing potential at a meeting of 300 securities analysts.
Behind the scenes, however, MK-869 was starting to unravel. True, many test subjects treated with the medication felt their hopelessness and anxiety lift. But so did nearly the same number who took a placebo, a look-alike pill made of milk sugar or another inert substance given to groups of volunteers in clinical trials to gauge how much more effective the real drug is by comparison. The fact that taking a faux drug can powerfully improve some people's health—the so-called placebo effect—has long been considered an embarrassment to the serious practice of pharmacology.
Ultimately, Merck's foray into the antidepressant market failed. In subsequent tests, MK-869 turned out to be no more effective than a placebo. In the jargon of the industry, the trials crossed the futility boundary.
MK-869 wasn't the only highly anticipated medical breakthrough to be undone in recent years by the placebo effect. From 2001 to 2006, the percentage of new products cut from development after Phase II clinical trials, when drugs are first tested against placebo, rose by 20 percent. The failure rate in more extensive Phase III trials increased by 11 percent, mainly due to surprisingly poor showings against placebo. Despite historic levels of industry investment in R&D, the US Food and Drug Administration approved only 19 first-of-their-kind remedies in 2007—the fewest since 1983—and just 24 in 2008. Half of all drugs that fail in late-stage trials drop out of the pipeline due to their inability to beat sugar pills.
The upshot is fewer new medicines available to ailing patients and more financial woes for the beleaguered pharmaceutical industry. Last November, a new type of gene therapy for Parkinson's disease, championed by the Michael J. Fox Foundation, was abruptly withdrawn from Phase II trials after unexpectedly tanking against placebo. A stem-cell startup called Osiris Therapeutics got a drubbing on Wall Street in March, when it suspended trials of its pill for Crohn's disease, an intestinal ailment, citing an "unusually high" response to placebo. Two days later, Eli Lilly broke off testing of a much-touted new drug for schizophrenia when volunteers showed double the expected level of placebo response.
It's not only trials of new drugs that are crossing the futility boundary. Some products that have been on the market for decades, like Prozac, are faltering in more recent follow-up tests. In many cases, these are the compounds that, in the late '90s, made Big Pharma more profitable than Big Oil. But if these same drugs were vetted now, the FDA might not approve some of them. Two comprehensive analyses of antidepressant trials have uncovered a dramatic increase in placebo response since the 1980s. One estimated that the so-called effect size (a measure of statistical significance) in placebo groups had nearly doubled over that time.
It's not that the old meds are getting weaker, drug developers say. It's as if the placebo effect is somehow getting stronger.
The fact that an increasing number of medications are unable to beat sugar pills has thrown the industry into crisis. The stakes could hardly be higher. In today's economy, the fate of a long-established company can hang on the outcome of a handful of tests.
Why are inert pills suddenly overwhelming promising new drugs and established medicines alike? The reasons are only just beginning to be understood. A network of independent researchers is doggedly uncovering the inner workings—and potential therapeutic applications—of the placebo effect. At the same time, drugmakers are realizing they need to fully understand the mechanisms behind it so they can design trials that differentiate more clearly between the beneficial effects of their products and the body's innate ability to heal itself. A special task force of the Foundation for the National Institutes of Health is seeking to stem the crisis by quietly undertaking one of the most ambitious data-sharing efforts in the history of the drug industry. After decades in the jungles of fringe science, the placebo effect has become the elephant in the boardroom.
The roots of the placebo problem can be traced to a lie told by an Army nurse during World War II as Allied forces stormed the beaches of southern Italy. The nurse was assisting an anesthetist named Henry Beecher, who was tending to US troops under heavy German bombardment. When the morphine supply ran low, the nurse assured a wounded soldier that he was getting a shot of potent painkiller, though her syringe contained only salt water. Amazingly, the bogus injection relieved the soldier's agony and prevented the onset of shock.
Returning to his post at Harvard after the war, Beecher became one of the nation's leading medical reformers. Inspired by the nurse's healing act of deception, he launched a crusade to promote a method of testing new medicines to find out whether they were truly effective. At the time, the process for vetting drugs was sloppy at best: Pharmaceutical companies would simply dose volunteers with an experimental agent until the side effects swamped the presumed benefits. Beecher proposed that if test subjects could be compared to a group that received a placebo, health officials would finally have an impartial way to determine whether a medicine was actually responsible for making a patient better.
In a 1955 paper titled "The Powerful Placebo," published in The Journal of the American Medical Association, Beecher described how the placebo effect had undermined the results of more than a dozen trials by causing improvement that was mistakenly attributed to the drugs being tested. He demonstrated that trial volunteers who got real medication were also subject to placebo effects; the act of taking a pill was itself somehow therapeutic, boosting the curative power of the medicine. Only by subtracting the improvement in a placebo control group could the actual value of the drug be calculated.
The article caused a sensation. By 1962, reeling from news of birth defects caused by a drug called thalidomide, Congress amended the Food, Drug, and Cosmetic Act, requiring trials to include enhanced safety testing and placebo control groups. Volunteers would be assigned randomly to receive either medicine or a sugar pill, and neither doctor nor patient would know the difference until the trial was over. Beecher's double-blind, placebo-controlled, randomized clinical trial—or RCT—was enshrined as the gold standard of the emerging pharmaceutical industry. Today, to win FDA approval, a new medication must beat placebo in at least two authenticated trials.
Beecher's prescription helped cure the medical establishment of outright quackery, but it had an insidious side effect. By casting placebo as the villain in RCTs, he ended up stigmatizing one of his most important discoveries. The fact that even dummy capsules can kick-start the body's recovery engine became a problem for drug developers to overcome, rather than a phenomenon that could guide doctors toward a better understanding of the healing process and how to drive it most effectively.
In his eagerness to promote his template for clinical trials, Beecher also overreached by seeing the placebo effect at work in curing ailments like the common cold, which wane with no intervention at all. But the triumph of Beecher's gold standard was a generation of safer medications that worked for nearly everyone. Anthracyclines don't require an oncologist with a genial bedside manner to slow the growth of tumors.
What Beecher didn't foresee, however, was the explosive growth of the pharmaceutical industry. The blockbuster success of mood drugs in the '80s and '90s emboldened Big Pharma to promote remedies for a growing panoply of disorders that are intimately related to higher brain function. By attempting to dominate the central nervous system, Big Pharma gambled its future on treating ailments that have turned out to be particularly susceptible to the placebo effect.
The tall, rusty-haired son of a country doctor, William Potter, 64, has spent most of his life treating mental illness—first as a psychiatrist at the National Institute of Mental Health and then as a drug developer. A decade ago, he took a job at Lilly's neuroscience labs. There, working on new antidepressants and antianxiety meds, he became one of the first researchers to glimpse the approaching storm.
To test products internally, pharmaceutical companies routinely run trials in which a long-established medication and an experimental one compete against each other as well as against a placebo. As head of Lilly's early-stage psychiatric drug development in the late '90s, Potter saw that even durable warhorses like Prozac, which had been on the market for years, were being overtaken by dummy pills in more recent tests. The company's next-generation antidepressants were faring badly, too, doing no better than placebo in seven out of 10 trials.
As a psychiatrist, Potter knew that some patients really do seem to get healthier for reasons that have more to do with a doctor's empathy than with the contents of a pill. But it baffled him that drugs he'd been prescribing for years seemed to be struggling to prove their effectiveness. Thinking that something crucial may have been overlooked, Potter tapped an IT geek named David DeBrota to help him comb through the Lilly database of published and unpublished trials—including those that the company had kept secret because of high placebo response. They aggregated the findings from decades of antidepressant trials, looking for patterns and trying to see what was changing over time. What they found challenged some of the industry's basic assumptions about its drug-vetting process.
Assumption number one was that if a trial were managed correctly, a medication would perform as well or badly in a Phoenix hospital as in a Bangalore clinic. Potter discovered, however, that geographic location alone could determine whether a drug bested placebo or crossed the futility boundary. By the late '90s, for example, the classic antianxiety drug diazepam (also known as Valium) was still beating placebo in France and Belgium. But when the drug was tested in the US, it was likely to fail. Conversely, Prozac performed better in America than it did in western Europe and South Africa. It was an unsettling prospect: FDA approval could hinge on where the company chose to conduct a trial.
Mistaken assumption number two was that the standard tests used to gauge volunteers' improvement in trials yielded consistent results. Potter and his colleagues discovered that ratings by trial observers varied significantly from one testing site to another. It was like finding out that the judges in a tight race each had a different idea about the placement of the finish line.
Potter and DeBrota's data-mining also revealed that even superbly managed trials were subject to runaway placebo effects. But exactly why any of this was happening remained elusive. "We were able to identify many of the core issues in play," Potter says. "But there was no clear answer to the problem." Convinced that what Lilly was facing was too complex for any one pharmaceutical house to unravel on its own, he came up with a plan to break down the firewalls between researchers across the industry, enabling them to share data in "pre-competitive space."
After prodding by Potter and others, the NIH focused on the issue in 2000, hosting a three-day conference in Washington. For the first time in medical history, more than 500 drug developers, doctors, academics, and trial designers put their heads together to examine the role of the placebo effect in clinical trials and healing in general.
Potter's ambitious plan for a collaborative approach to the problem eventually ran into its own futility boundary: No one would pay for it. And drug companies don't share data, they hoard it. But the NIH conference launched a new wave of placebo research in academic labs in the US and Italy that would make significant progress toward solving the mystery of what was happening in clinical trials.
Visitors to Fabrizio Benedetti's clinic at the University of Turin are asked never to say the P-word around the med students who sign up for his experiments. For all the volunteers know, the trim, soft-spoken neuroscientist is hard at work concocting analgesic skin creams and methods for enhancing athletic performance.
One recent afternoon in his lab, a young soccer player grimaced with exertion while doing leg curls on a weight machine. Benedetti and his colleagues were exploring the potential of using Pavlovian conditioning to give athletes a competitive edge undetectable by anti-doping authorities. A player would receive doses of a performance-enhancing drug for weeks and then a jolt of placebo just before competition.
Benedetti, 53, first became interested in placebos in the mid-'90s, while researching pain. He was surprised that some of the test subjects in his placebo groups seemed to suffer less than those on active drugs. But scientific interest in this phenomenon, and the money to research it, were hard to come by. "The placebo effect was considered little more than a nuisance," he recalls. "Drug companies, physicians, and clinicians were not interested in understanding its mechanisms. They were concerned only with figuring out whether their drugs worked better."
Part of the problem was that response to placebo was considered a psychological trait related to neurosis and gullibility rather than a physiological phenomenon that could be scrutinized in the lab and manipulated for therapeutic benefit. But then Benedetti came across a study, done years earlier, that suggested the placebo effect had a neurological foundation. US scientists had found that a drug called naloxone blocks the pain-relieving power of placebo treatments. The brain produces its own analgesic compounds called opioids, released under conditions of stress, and naloxone blocks the action of these natural painkillers and their synthetic analogs. The study gave Benedetti the lead he needed to pursue his own research while running small clinical trials for drug companies.
Now, after 15 years of experimentation, he has succeeded in mapping many of the biochemical reactions responsible for the placebo effect, uncovering a broad repertoire of self-healing responses. Placebo-activated opioids, for example, not only relieve pain; they also modulate heart rate and respiration. The neurotransmitter dopamine, when released by placebo treatment, helps improve motor function in Parkinson's patients. Mechanisms like these can elevate mood, sharpen cognitive ability, alleviate digestive disorders, relieve insomnia, and limit the secretion of stress-related hormones like insulin and cortisol.
In one study, Benedetti found that Alzheimer's patients with impaired cognitive function get less pain relief from analgesic drugs than normal volunteers do. Using advanced methods of EEG analysis, he discovered that the connections between the patients' prefrontal lobes and their opioid systems had been damaged. Healthy volunteers feel the benefit of medication plus a placebo boost. Patients who are unable to formulate ideas about the future because of cortical deficits, however, feel only the effect of the drug itself. The experiment suggests that because Alzheimer's patients don't get the benefits of anticipating the treatment, they require higher doses of painkillers to experience normal levels of relief.
Benedetti often uses the phrase "placebo response" instead of placebo effect. By definition, inert pills have no effect, but under the right conditions they can act as a catalyst for what he calls the body's "endogenous health care system." Like any other internal network, the placebo response has limits. It can ease the discomfort of chemotherapy, but it won't stop the growth of tumors. It also works in reverse to produce the placebo's evil twin, the nocebo effect. For example, men taking a commonly prescribed prostate drug who were informed that the medication may cause sexual dysfunction were twice as likely to become impotent.
Further research by Benedetti and others showed that the promise of treatment activates areas of the brain involved in weighing the significance of events and the seriousness of threats. "If a fire alarm goes off and you see smoke, you know something bad is going to happen and you get ready to escape," explains Tor Wager, a neuroscientist at Columbia University. "Expectations about pain and pain relief work in a similar way. Placebo treatments tap into this system and orchestrate the responses in your brain and body accordingly."
In other words, one way that placebo aids recovery is by hacking the mind's ability to predict the future. We are constantly parsing the reactions of those around us—such as the tone a doctor uses to deliver a diagnosis—to generate more-accurate estimations of our fate. One of the most powerful placebogenic triggers is watching someone else experience the benefits of an alleged drug. Researchers call these social aspects of medicine the therapeutic ritual.
In a study last year, Harvard Medical School researcher Ted Kaptchuk devised a clever strategy for testing his volunteers' response to varying levels of therapeutic ritual. The study focused on irritable bowel syndrome, a painful disorder that costs more than $40 billion a year worldwide to treat. First the volunteers were placed randomly in one of three groups. One group was simply put on a waiting list; researchers know that some patients get better just because they sign up for a trial. Another group received placebo treatment from a clinician who declined to engage in small talk. Volunteers in the third group got the same sham treatment from a clinician who asked them questions about symptoms, outlined the causes of IBS, and displayed optimism about their condition.
What turns a dummy pill into a catalyst for relieving pain, anxiety, depression, sexual dysfunction, or the tremors of Parkinson's disease? The brain's own healing mechanisms, unleashed by the belief that a phony medication is the real thing. The most important ingredient in any placebo is the doctor's bedside manner, but according to research, the color of a tablet can boost the effectiveness even of genuine meds—or help convince a patient that a placebo is a potent remedy.—Steve Silberman
Yellow pills
make the most effective antidepressants, like little doses of pharmaceutical sunshine.
Red pills
can give you a more stimulating kick. Wake up, Neo.
The color green
reduces anxiety, adding more chill to the pill.
White tablets—
particularly those labeled "antacid"—are superior for soothing ulcers, even when they contain nothing but lactose.
More is better,
scientists say. Placebos taken four times a day deliver greater relief than those taken twice daily.
Branding matters.
Placebos stamped or packaged with widely recognized trademarks are more effective than "generic" placebos.
Clever names
can add a placebo boost to the physiological punch in real drugs. Viagra implies both vitality and an unstoppable Niagara of sexy.
Not surprisingly, the health of those in the third group improved most. In fact, just by participating in the trial, volunteers in this high-interaction group got as much relief as did people taking the two leading prescription drugs for IBS. And the benefits of their bogus treatment persisted for weeks afterward, contrary to the belief—widespread in the pharmaceutical industry—that the placebo response is short-lived.
Studies like this open the door to hybrid treatment strategies that exploit the placebo effect to make real drugs safer and more effective. Cancer patients undergoing rounds of chemotherapy often suffer from debilitating nocebo effects—such as anticipatory nausea—conditioned by their past experiences with the drugs. A team of German researchers has shown that these associations can be unlearned through the administration of placebo, making chemo easier to bear.
Meanwhile, the classic use of placebos in medicine—to boost the confidence of anxious patients—has been employed tacitly for ages. Nearly half of the doctors polled in a 2007 survey in Chicago admitted to prescribing medications they knew were ineffective for a patient's condition—or prescribing effective drugs in doses too low to produce actual benefit—in order to provoke a placebo response.
The main objections to more widespread placebo use in clinical practice are ethical, but the solutions to these conundrums can be surprisingly simple. Investigators told volunteers in one placebo study that the pills they were taking were "known to significantly reduce pain in some patients." The researchers weren't lying.
These new findings tell us that the body's response to certain types of medication is in constant flux, affected by expectations of treatment, conditioning, beliefs, and social cues.
For instance, the geographic variations in trial outcome that Potter uncovered begin to make sense in light of discoveries that the placebo response is highly sensitive to cultural differences. Anthropologist Daniel Moerman found that Germans are high placebo reactors in trials of ulcer drugs but low in trials of drugs for hypertension—an undertreated condition in Germany, where many people pop pills for herzinsuffizienz, or low blood pressure. Moreover, a pill's shape, size, branding, and price all influence its effects on the body. Soothing blue capsules make more effective tranquilizers than angry red ones, except among Italian men, for whom the color blue is associated with their national soccer team—Forza Azzurri!
But why would the placebo effect seem to be getting stronger worldwide? Part of the answer may be found in the drug industry's own success in marketing its products.
Potential trial volunteers in the US have been deluged with ads for prescription medications since 1997, when the FDA amended its policy on direct-to-consumer advertising. The secret of running an effective campaign, Saatchi & Saatchi's Jim Joseph told a trade journal last year, is associating a particular brand-name medication with other aspects of life that promote peace of mind: "Is it time with your children? Is it a good book curled up on the couch? Is it your favorite television show? Is it a little purple pill that helps you get rid of acid reflux?" By evoking such uplifting associations, researchers say, the ads set up the kind of expectations that induce a formidable placebo response.
The success of those ads in selling blockbuster drugs like antidepressants and statins also pushed trials offshore as therapeutic virgins—potential volunteers who were not already medicated with one or another drug—became harder to find. The contractors that manage trials for Big Pharma have moved aggressively into Africa, India, China, and the former Soviet Union. In these places, however, cultural dynamics can boost the placebo response in other ways. Doctors in these countries are paid to fill up trial rosters quickly, which may motivate them to recruit patients with milder forms of illness that yield more readily to placebo treatment. Furthermore, a patient's hope of getting better and expectation of expert care—the primary placebo triggers in the brain—are particularly acute in societies where volunteers are clamoring to gain access to the most basic forms of medicine. "The quality of care that placebo patients get in trials is far superior to the best insurance you get in America," says psychiatrist Arif Khan, principal investigator in hundreds of trials for companies like Pfizer and Bristol-Myers Squibb. "It's basically luxury care."
Big Pharma faces additional problems in beating placebo when it comes to psychiatric drugs. One is to accurately define the nature of mental illness. The litmus test of drug efficacy in antidepressant trials is a questionnaire called the Hamilton Depression Rating Scale. The HAM-D was created nearly 50 years ago based on a study of major depressive disorder in patients confined to asylums. Few trial volunteers now suffer from that level of illness. In fact, many experts are starting to wonder if what drug companies now call depression is even the same disease that the HAM-D was designed to diagnose.
Existing tests also may not be appropriate for diagnosing disorders like social anxiety and premenstrual dysphoria—the very types of chronic, fuzzily defined conditions that the drug industry started targeting in the '90s, when the placebo problem began escalating. The neurological foundation of these illnesses is still being debated, making it even harder for drug companies to come up with effective treatments.
What all of these disorders have in common, however, is that they engage the higher cortical centers that generate beliefs and expectations, interpret social cues, and anticipate rewards. So do chronic pain, sexual dysfunction, Parkinson's, and many other ailments that respond robustly to placebo treatment. To avoid investing in failure, researchers say, pharmaceutical companies will need to adopt new ways of vetting drugs that route around the brain's own centralized network for healing.
Ten years and billions of R&D dollars after William Potter first sounded the alarm about the placebo effect, his message has finally gotten through. In the spring, Potter, who is now a VP at Merck, helped rev up a massive data-gathering effort called the Placebo Response Drug Trials Survey.
Under the auspices of the NIH, Potter and his colleagues are acquiring decades of trial data—including blood and DNA samples—to determine which variables are responsible for the apparent rise in the placebo effect. Merck, Lilly, Pfizer, AstraZeneca, GlaxoSmithKline, Sanofi-Aventis, Johnson & Johnson, and other major firms are funding the study, and the process of scrubbing volunteers' names and other personal information from the database is about to begin.
In typically secretive industry fashion, the existence of the project itself is being kept under wraps. NIH staffers are willing to talk about it only anonymously, concerned about offending the companies paying for it.
For Potter, who used to ride along with his father on house calls in Indiana, the significance of the survey goes beyond Big Pharma's finally admitting it has a placebo problem. It also marks the twilight of an era when the drug industry was confident that its products were strong enough to cure illness by themselves.
"Before I routinely prescribed antidepressants, I would do more psychotherapy for mildly depressed patients," says the veteran of hundreds of drug trials. "Today we would say I was trying to engage components of the placebo response—and those patients got better. To really do the best for your patients, you want the best placebo response plus the best drug response."
The pharma crisis has also finally brought together the two parallel streams of placebo research—academic and industrial. Pfizer has asked Fabrizio Benedetti to help the company figure out why two of its pain drugs keep failing. Ted Kaptchuk is developing ways to distinguish drug response more clearly from placebo response for another pharma house that he declines to name. Both are exploring innovative trial models that treat the placebo effect as more than just statistical noise competing with the active drug.
Benedetti has helped design a protocol for minimizing volunteers' expectations that he calls "open/hidden." In standard trials, the act of taking a pill or receiving an injection activates the placebo response. In open/hidden trials, drugs and placebos are given to some test subjects in the usual way and to others at random intervals through an IV line controlled by a concealed computer. Drugs that work only when the patient knows they're being administered are placebos themselves.
Ironically, Big Pharma's attempt to dominate the central nervous system has ended up revealing how powerful the brain really is. The placebo response doesn't care if the catalyst for healing is a triumph of pharmacology, a compassionate therapist, or a syringe of salt water. All it requires is a reasonable expectation of getting better. That's potent medicine.
Contributing editor Steve Silberman (steve@stevesilberman.com) wrote about the hunt for Jim Gray in issue 15.08.
Merck was in trouble. In 2002, the pharmaceutical giant was falling behind its rivals in sales. Even worse, patents on five blockbuster drugs were about to expire, which would allow cheaper generics to flood the market. The company hadn't introduced a truly new product in three years, and its stock price was plummeting.In interviews with the press, Edward Scolnick, Merck's research director, laid out his battle plan to restore the firm to preeminence. Key to his strategy was expanding the company's reach into the antidepressant market, where Merck had lagged while competitors like Pfizer and GlaxoSmithKline created some of the best-selling drugs in the world. "To remain dominant in the future," he told Forbes, "we need to dominate the central nervous system."
His plan hinged on the success of an experimental antidepressant codenamed MK-869. Still in clinical trials, it looked like every pharma executive's dream: a new kind of medication that exploited brain chemistry in innovative ways to promote feelings of well-being. The drug tested brilliantly early on, with minimal side effects, and Merck touted its game-changing potential at a meeting of 300 securities analysts.
Behind the scenes, however, MK-869 was starting to unravel. True, many test subjects treated with the medication felt their hopelessness and anxiety lift. But so did nearly the same number who took a placebo, a look-alike pill made of milk sugar or another inert substance given to groups of volunteers in clinical trials to gauge how much more effective the real drug is by comparison. The fact that taking a faux drug can powerfully improve some people's health—the so-called placebo effect—has long been considered an embarrassment to the serious practice of pharmacology.
Ultimately, Merck's foray into the antidepressant market failed. In subsequent tests, MK-869 turned out to be no more effective than a placebo. In the jargon of the industry, the trials crossed the futility boundary.
MK-869 wasn't the only highly anticipated medical breakthrough to be undone in recent years by the placebo effect. From 2001 to 2006, the percentage of new products cut from development after Phase II clinical trials, when drugs are first tested against placebo, rose by 20 percent. The failure rate in more extensive Phase III trials increased by 11 percent, mainly due to surprisingly poor showings against placebo. Despite historic levels of industry investment in R&D, the US Food and Drug Administration approved only 19 first-of-their-kind remedies in 2007—the fewest since 1983—and just 24 in 2008. Half of all drugs that fail in late-stage trials drop out of the pipeline due to their inability to beat sugar pills.
The upshot is fewer new medicines available to ailing patients and more financial woes for the beleaguered pharmaceutical industry. Last November, a new type of gene therapy for Parkinson's disease, championed by the Michael J. Fox Foundation, was abruptly withdrawn from Phase II trials after unexpectedly tanking against placebo. A stem-cell startup called Osiris Therapeutics got a drubbing on Wall Street in March, when it suspended trials of its pill for Crohn's disease, an intestinal ailment, citing an "unusually high" response to placebo. Two days later, Eli Lilly broke off testing of a much-touted new drug for schizophrenia when volunteers showed double the expected level of placebo response.
It's not only trials of new drugs that are crossing the futility boundary. Some products that have been on the market for decades, like Prozac, are faltering in more recent follow-up tests. In many cases, these are the compounds that, in the late '90s, made Big Pharma more profitable than Big Oil. But if these same drugs were vetted now, the FDA might not approve some of them. Two comprehensive analyses of antidepressant trials have uncovered a dramatic increase in placebo response since the 1980s. One estimated that the so-called effect size (a measure of statistical significance) in placebo groups had nearly doubled over that time.
It's not that the old meds are getting weaker, drug developers say. It's as if the placebo effect is somehow getting stronger.
The fact that an increasing number of medications are unable to beat sugar pills has thrown the industry into crisis. The stakes could hardly be higher. In today's economy, the fate of a long-established company can hang on the outcome of a handful of tests.
Why are inert pills suddenly overwhelming promising new drugs and established medicines alike? The reasons are only just beginning to be understood. A network of independent researchers is doggedly uncovering the inner workings—and potential therapeutic applications—of the placebo effect. At the same time, drugmakers are realizing they need to fully understand the mechanisms behind it so they can design trials that differentiate more clearly between the beneficial effects of their products and the body's innate ability to heal itself. A special task force of the Foundation for the National Institutes of Health is seeking to stem the crisis by quietly undertaking one of the most ambitious data-sharing efforts in the history of the drug industry. After decades in the jungles of fringe science, the placebo effect has become the elephant in the boardroom.
The roots of the placebo problem can be traced to a lie told by an Army nurse during World War II as Allied forces stormed the beaches of southern Italy. The nurse was assisting an anesthetist named Henry Beecher, who was tending to US troops under heavy German bombardment. When the morphine supply ran low, the nurse assured a wounded soldier that he was getting a shot of potent painkiller, though her syringe contained only salt water. Amazingly, the bogus injection relieved the soldier's agony and prevented the onset of shock.
Returning to his post at Harvard after the war, Beecher became one of the nation's leading medical reformers. Inspired by the nurse's healing act of deception, he launched a crusade to promote a method of testing new medicines to find out whether they were truly effective. At the time, the process for vetting drugs was sloppy at best: Pharmaceutical companies would simply dose volunteers with an experimental agent until the side effects swamped the presumed benefits. Beecher proposed that if test subjects could be compared to a group that received a placebo, health officials would finally have an impartial way to determine whether a medicine was actually responsible for making a patient better.
In a 1955 paper titled "The Powerful Placebo," published in The Journal of the American Medical Association, Beecher described how the placebo effect had undermined the results of more than a dozen trials by causing improvement that was mistakenly attributed to the drugs being tested. He demonstrated that trial volunteers who got real medication were also subject to placebo effects; the act of taking a pill was itself somehow therapeutic, boosting the curative power of the medicine. Only by subtracting the improvement in a placebo control group could the actual value of the drug be calculated.
The article caused a sensation. By 1962, reeling from news of birth defects caused by a drug called thalidomide, Congress amended the Food, Drug, and Cosmetic Act, requiring trials to include enhanced safety testing and placebo control groups. Volunteers would be assigned randomly to receive either medicine or a sugar pill, and neither doctor nor patient would know the difference until the trial was over. Beecher's double-blind, placebo-controlled, randomized clinical trial—or RCT—was enshrined as the gold standard of the emerging pharmaceutical industry. Today, to win FDA approval, a new medication must beat placebo in at least two authenticated trials.
Beecher's prescription helped cure the medical establishment of outright quackery, but it had an insidious side effect. By casting placebo as the villain in RCTs, he ended up stigmatizing one of his most important discoveries. The fact that even dummy capsules can kick-start the body's recovery engine became a problem for drug developers to overcome, rather than a phenomenon that could guide doctors toward a better understanding of the healing process and how to drive it most effectively.
In his eagerness to promote his template for clinical trials, Beecher also overreached by seeing the placebo effect at work in curing ailments like the common cold, which wane with no intervention at all. But the triumph of Beecher's gold standard was a generation of safer medications that worked for nearly everyone. Anthracyclines don't require an oncologist with a genial bedside manner to slow the growth of tumors.
What Beecher didn't foresee, however, was the explosive growth of the pharmaceutical industry. The blockbuster success of mood drugs in the '80s and '90s emboldened Big Pharma to promote remedies for a growing panoply of disorders that are intimately related to higher brain function. By attempting to dominate the central nervous system, Big Pharma gambled its future on treating ailments that have turned out to be particularly susceptible to the placebo effect.
The tall, rusty-haired son of a country doctor, William Potter, 64, has spent most of his life treating mental illness—first as a psychiatrist at the National Institute of Mental Health and then as a drug developer. A decade ago, he took a job at Lilly's neuroscience labs. There, working on new antidepressants and antianxiety meds, he became one of the first researchers to glimpse the approaching storm.
To test products internally, pharmaceutical companies routinely run trials in which a long-established medication and an experimental one compete against each other as well as against a placebo. As head of Lilly's early-stage psychiatric drug development in the late '90s, Potter saw that even durable warhorses like Prozac, which had been on the market for years, were being overtaken by dummy pills in more recent tests. The company's next-generation antidepressants were faring badly, too, doing no better than placebo in seven out of 10 trials.
As a psychiatrist, Potter knew that some patients really do seem to get healthier for reasons that have more to do with a doctor's empathy than with the contents of a pill. But it baffled him that drugs he'd been prescribing for years seemed to be struggling to prove their effectiveness. Thinking that something crucial may have been overlooked, Potter tapped an IT geek named David DeBrota to help him comb through the Lilly database of published and unpublished trials—including those that the company had kept secret because of high placebo response. They aggregated the findings from decades of antidepressant trials, looking for patterns and trying to see what was changing over time. What they found challenged some of the industry's basic assumptions about its drug-vetting process.
Assumption number one was that if a trial were managed correctly, a medication would perform as well or badly in a Phoenix hospital as in a Bangalore clinic. Potter discovered, however, that geographic location alone could determine whether a drug bested placebo or crossed the futility boundary. By the late '90s, for example, the classic antianxiety drug diazepam (also known as Valium) was still beating placebo in France and Belgium. But when the drug was tested in the US, it was likely to fail. Conversely, Prozac performed better in America than it did in western Europe and South Africa. It was an unsettling prospect: FDA approval could hinge on where the company chose to conduct a trial.
Mistaken assumption number two was that the standard tests used to gauge volunteers' improvement in trials yielded consistent results. Potter and his colleagues discovered that ratings by trial observers varied significantly from one testing site to another. It was like finding out that the judges in a tight race each had a different idea about the placement of the finish line.
Potter and DeBrota's data-mining also revealed that even superbly managed trials were subject to runaway placebo effects. But exactly why any of this was happening remained elusive. "We were able to identify many of the core issues in play," Potter says. "But there was no clear answer to the problem." Convinced that what Lilly was facing was too complex for any one pharmaceutical house to unravel on its own, he came up with a plan to break down the firewalls between researchers across the industry, enabling them to share data in "pre-competitive space."
After prodding by Potter and others, the NIH focused on the issue in 2000, hosting a three-day conference in Washington. For the first time in medical history, more than 500 drug developers, doctors, academics, and trial designers put their heads together to examine the role of the placebo effect in clinical trials and healing in general.
Potter's ambitious plan for a collaborative approach to the problem eventually ran into its own futility boundary: No one would pay for it. And drug companies don't share data, they hoard it. But the NIH conference launched a new wave of placebo research in academic labs in the US and Italy that would make significant progress toward solving the mystery of what was happening in clinical trials.
Visitors to Fabrizio Benedetti's clinic at the University of Turin are asked never to say the P-word around the med students who sign up for his experiments. For all the volunteers know, the trim, soft-spoken neuroscientist is hard at work concocting analgesic skin creams and methods for enhancing athletic performance.
One recent afternoon in his lab, a young soccer player grimaced with exertion while doing leg curls on a weight machine. Benedetti and his colleagues were exploring the potential of using Pavlovian conditioning to give athletes a competitive edge undetectable by anti-doping authorities. A player would receive doses of a performance-enhancing drug for weeks and then a jolt of placebo just before competition.
Benedetti, 53, first became interested in placebos in the mid-'90s, while researching pain. He was surprised that some of the test subjects in his placebo groups seemed to suffer less than those on active drugs. But scientific interest in this phenomenon, and the money to research it, were hard to come by. "The placebo effect was considered little more than a nuisance," he recalls. "Drug companies, physicians, and clinicians were not interested in understanding its mechanisms. They were concerned only with figuring out whether their drugs worked better."
Part of the problem was that response to placebo was considered a psychological trait related to neurosis and gullibility rather than a physiological phenomenon that could be scrutinized in the lab and manipulated for therapeutic benefit. But then Benedetti came across a study, done years earlier, that suggested the placebo effect had a neurological foundation. US scientists had found that a drug called naloxone blocks the pain-relieving power of placebo treatments. The brain produces its own analgesic compounds called opioids, released under conditions of stress, and naloxone blocks the action of these natural painkillers and their synthetic analogs. The study gave Benedetti the lead he needed to pursue his own research while running small clinical trials for drug companies.
Now, after 15 years of experimentation, he has succeeded in mapping many of the biochemical reactions responsible for the placebo effect, uncovering a broad repertoire of self-healing responses. Placebo-activated opioids, for example, not only relieve pain; they also modulate heart rate and respiration. The neurotransmitter dopamine, when released by placebo treatment, helps improve motor function in Parkinson's patients. Mechanisms like these can elevate mood, sharpen cognitive ability, alleviate digestive disorders, relieve insomnia, and limit the secretion of stress-related hormones like insulin and cortisol.
In one study, Benedetti found that Alzheimer's patients with impaired cognitive function get less pain relief from analgesic drugs than normal volunteers do. Using advanced methods of EEG analysis, he discovered that the connections between the patients' prefrontal lobes and their opioid systems had been damaged. Healthy volunteers feel the benefit of medication plus a placebo boost. Patients who are unable to formulate ideas about the future because of cortical deficits, however, feel only the effect of the drug itself. The experiment suggests that because Alzheimer's patients don't get the benefits of anticipating the treatment, they require higher doses of painkillers to experience normal levels of relief.
Benedetti often uses the phrase "placebo response" instead of placebo effect. By definition, inert pills have no effect, but under the right conditions they can act as a catalyst for what he calls the body's "endogenous health care system." Like any other internal network, the placebo response has limits. It can ease the discomfort of chemotherapy, but it won't stop the growth of tumors. It also works in reverse to produce the placebo's evil twin, the nocebo effect. For example, men taking a commonly prescribed prostate drug who were informed that the medication may cause sexual dysfunction were twice as likely to become impotent.
Further research by Benedetti and others showed that the promise of treatment activates areas of the brain involved in weighing the significance of events and the seriousness of threats. "If a fire alarm goes off and you see smoke, you know something bad is going to happen and you get ready to escape," explains Tor Wager, a neuroscientist at Columbia University. "Expectations about pain and pain relief work in a similar way. Placebo treatments tap into this system and orchestrate the responses in your brain and body accordingly."
In other words, one way that placebo aids recovery is by hacking the mind's ability to predict the future. We are constantly parsing the reactions of those around us—such as the tone a doctor uses to deliver a diagnosis—to generate more-accurate estimations of our fate. One of the most powerful placebogenic triggers is watching someone else experience the benefits of an alleged drug. Researchers call these social aspects of medicine the therapeutic ritual.
In a study last year, Harvard Medical School researcher Ted Kaptchuk devised a clever strategy for testing his volunteers' response to varying levels of therapeutic ritual. The study focused on irritable bowel syndrome, a painful disorder that costs more than $40 billion a year worldwide to treat. First the volunteers were placed randomly in one of three groups. One group was simply put on a waiting list; researchers know that some patients get better just because they sign up for a trial. Another group received placebo treatment from a clinician who declined to engage in small talk. Volunteers in the third group got the same sham treatment from a clinician who asked them questions about symptoms, outlined the causes of IBS, and displayed optimism about their condition.
Rx for Success
What turns a dummy pill into a catalyst for relieving pain, anxiety, depression, sexual dysfunction, or the tremors of Parkinson's disease? The brain's own healing mechanisms, unleashed by the belief that a phony medication is the real thing. The most important ingredient in any placebo is the doctor's bedside manner, but according to research, the color of a tablet can boost the effectiveness even of genuine meds—or help convince a patient that a placebo is a potent remedy.—Steve Silberman
Yellow pills
make the most effective antidepressants, like little doses of pharmaceutical sunshine.
Red pills
can give you a more stimulating kick. Wake up, Neo.
The color green
reduces anxiety, adding more chill to the pill.
White tablets—
particularly those labeled "antacid"—are superior for soothing ulcers, even when they contain nothing but lactose.
More is better,
scientists say. Placebos taken four times a day deliver greater relief than those taken twice daily.
Branding matters.
Placebos stamped or packaged with widely recognized trademarks are more effective than "generic" placebos.
Clever names
can add a placebo boost to the physiological punch in real drugs. Viagra implies both vitality and an unstoppable Niagara of sexy.
Not surprisingly, the health of those in the third group improved most. In fact, just by participating in the trial, volunteers in this high-interaction group got as much relief as did people taking the two leading prescription drugs for IBS. And the benefits of their bogus treatment persisted for weeks afterward, contrary to the belief—widespread in the pharmaceutical industry—that the placebo response is short-lived.
Studies like this open the door to hybrid treatment strategies that exploit the placebo effect to make real drugs safer and more effective. Cancer patients undergoing rounds of chemotherapy often suffer from debilitating nocebo effects—such as anticipatory nausea—conditioned by their past experiences with the drugs. A team of German researchers has shown that these associations can be unlearned through the administration of placebo, making chemo easier to bear.
Meanwhile, the classic use of placebos in medicine—to boost the confidence of anxious patients—has been employed tacitly for ages. Nearly half of the doctors polled in a 2007 survey in Chicago admitted to prescribing medications they knew were ineffective for a patient's condition—or prescribing effective drugs in doses too low to produce actual benefit—in order to provoke a placebo response.
The main objections to more widespread placebo use in clinical practice are ethical, but the solutions to these conundrums can be surprisingly simple. Investigators told volunteers in one placebo study that the pills they were taking were "known to significantly reduce pain in some patients." The researchers weren't lying.
These new findings tell us that the body's response to certain types of medication is in constant flux, affected by expectations of treatment, conditioning, beliefs, and social cues.
For instance, the geographic variations in trial outcome that Potter uncovered begin to make sense in light of discoveries that the placebo response is highly sensitive to cultural differences. Anthropologist Daniel Moerman found that Germans are high placebo reactors in trials of ulcer drugs but low in trials of drugs for hypertension—an undertreated condition in Germany, where many people pop pills for herzinsuffizienz, or low blood pressure. Moreover, a pill's shape, size, branding, and price all influence its effects on the body. Soothing blue capsules make more effective tranquilizers than angry red ones, except among Italian men, for whom the color blue is associated with their national soccer team—Forza Azzurri!
But why would the placebo effect seem to be getting stronger worldwide? Part of the answer may be found in the drug industry's own success in marketing its products.
Potential trial volunteers in the US have been deluged with ads for prescription medications since 1997, when the FDA amended its policy on direct-to-consumer advertising. The secret of running an effective campaign, Saatchi & Saatchi's Jim Joseph told a trade journal last year, is associating a particular brand-name medication with other aspects of life that promote peace of mind: "Is it time with your children? Is it a good book curled up on the couch? Is it your favorite television show? Is it a little purple pill that helps you get rid of acid reflux?" By evoking such uplifting associations, researchers say, the ads set up the kind of expectations that induce a formidable placebo response.
The success of those ads in selling blockbuster drugs like antidepressants and statins also pushed trials offshore as therapeutic virgins—potential volunteers who were not already medicated with one or another drug—became harder to find. The contractors that manage trials for Big Pharma have moved aggressively into Africa, India, China, and the former Soviet Union. In these places, however, cultural dynamics can boost the placebo response in other ways. Doctors in these countries are paid to fill up trial rosters quickly, which may motivate them to recruit patients with milder forms of illness that yield more readily to placebo treatment. Furthermore, a patient's hope of getting better and expectation of expert care—the primary placebo triggers in the brain—are particularly acute in societies where volunteers are clamoring to gain access to the most basic forms of medicine. "The quality of care that placebo patients get in trials is far superior to the best insurance you get in America," says psychiatrist Arif Khan, principal investigator in hundreds of trials for companies like Pfizer and Bristol-Myers Squibb. "It's basically luxury care."
Big Pharma faces additional problems in beating placebo when it comes to psychiatric drugs. One is to accurately define the nature of mental illness. The litmus test of drug efficacy in antidepressant trials is a questionnaire called the Hamilton Depression Rating Scale. The HAM-D was created nearly 50 years ago based on a study of major depressive disorder in patients confined to asylums. Few trial volunteers now suffer from that level of illness. In fact, many experts are starting to wonder if what drug companies now call depression is even the same disease that the HAM-D was designed to diagnose.
Existing tests also may not be appropriate for diagnosing disorders like social anxiety and premenstrual dysphoria—the very types of chronic, fuzzily defined conditions that the drug industry started targeting in the '90s, when the placebo problem began escalating. The neurological foundation of these illnesses is still being debated, making it even harder for drug companies to come up with effective treatments.
What all of these disorders have in common, however, is that they engage the higher cortical centers that generate beliefs and expectations, interpret social cues, and anticipate rewards. So do chronic pain, sexual dysfunction, Parkinson's, and many other ailments that respond robustly to placebo treatment. To avoid investing in failure, researchers say, pharmaceutical companies will need to adopt new ways of vetting drugs that route around the brain's own centralized network for healing.
Ten years and billions of R&D dollars after William Potter first sounded the alarm about the placebo effect, his message has finally gotten through. In the spring, Potter, who is now a VP at Merck, helped rev up a massive data-gathering effort called the Placebo Response Drug Trials Survey.
Under the auspices of the NIH, Potter and his colleagues are acquiring decades of trial data—including blood and DNA samples—to determine which variables are responsible for the apparent rise in the placebo effect. Merck, Lilly, Pfizer, AstraZeneca, GlaxoSmithKline, Sanofi-Aventis, Johnson & Johnson, and other major firms are funding the study, and the process of scrubbing volunteers' names and other personal information from the database is about to begin.
In typically secretive industry fashion, the existence of the project itself is being kept under wraps. NIH staffers are willing to talk about it only anonymously, concerned about offending the companies paying for it.
For Potter, who used to ride along with his father on house calls in Indiana, the significance of the survey goes beyond Big Pharma's finally admitting it has a placebo problem. It also marks the twilight of an era when the drug industry was confident that its products were strong enough to cure illness by themselves.
"Before I routinely prescribed antidepressants, I would do more psychotherapy for mildly depressed patients," says the veteran of hundreds of drug trials. "Today we would say I was trying to engage components of the placebo response—and those patients got better. To really do the best for your patients, you want the best placebo response plus the best drug response."
The pharma crisis has also finally brought together the two parallel streams of placebo research—academic and industrial. Pfizer has asked Fabrizio Benedetti to help the company figure out why two of its pain drugs keep failing. Ted Kaptchuk is developing ways to distinguish drug response more clearly from placebo response for another pharma house that he declines to name. Both are exploring innovative trial models that treat the placebo effect as more than just statistical noise competing with the active drug.
Benedetti has helped design a protocol for minimizing volunteers' expectations that he calls "open/hidden." In standard trials, the act of taking a pill or receiving an injection activates the placebo response. In open/hidden trials, drugs and placebos are given to some test subjects in the usual way and to others at random intervals through an IV line controlled by a concealed computer. Drugs that work only when the patient knows they're being administered are placebos themselves.
Ironically, Big Pharma's attempt to dominate the central nervous system has ended up revealing how powerful the brain really is. The placebo response doesn't care if the catalyst for healing is a triumph of pharmacology, a compassionate therapist, or a syringe of salt water. All it requires is a reasonable expectation of getting better. That's potent medicine.
Contributing editor Steve Silberman (steve@stevesilberman.com) wrote about the hunt for Jim Gray in issue 15.08.
Pfizer Corporate Integrity Agreement 2009
Guess how much it will cost Pfizer to not comply fully with this corporate integrity agreement the U.S. Department of Justice is so proud of?
A billion dollars? Nope.
A million dollars? Nope.
Correct answer: $1,000 bucks per day. See page 52.
Feel free to compare with how Pfizer sold the last corporate integrity agreement internally:
Living With a Corporate Integrity Agreement -
Guess that didn't work, since we know can view Pfizer's third agreement. How many more will there be? Five? Fifteen? Fifty?
A billion dollars? Nope.
A million dollars? Nope.
Correct answer: $1,000 bucks per day. See page 52.
Feel free to compare with how Pfizer sold the last corporate integrity agreement internally:
Living With a Corporate Integrity Agreement -
Guess that didn't work, since we know can view Pfizer's third agreement. How many more will there be? Five? Fifteen? Fifty?
Thursday, September 03, 2009
Wednesday, September 02, 2009
Video: Department of Justice press conference on Pfizer fraud
Pfizer Inc., the world's largest drug maker, will pay a record $2.3 billion civil and criminal penalty over unlawful prescription drug promotions, the Justice Department announced Sept. 2.
Justice Department Announces Largest Health Care Fraud Settlement in Its History: Pfizer to Pay $2.3 Billion for Fraudulent Marketing
WASHINGTON – American pharmaceutical giant Pfizer Inc. and its subsidiary Pharmacia & Upjohn Company Inc. (hereinafter together "Pfizer") have agreed to pay $2.3 billion, the largest health care fraud settlement in the history of the Department of Justice, to resolve criminal and civil liability arising from the illegal promotion of certain pharmaceutical products, the Justice Department announced today.
Pharmacia & Upjohn Company has agreed to plead guilty to a felony violation of the Food, Drug and Cosmetic Act for misbranding Bextra with the intent to defraud or mislead. Bextra is an anti-inflammatory drug that Pfizer pulled from the market in 2005. Under the provisions of the Food, Drug and Cosmetic Act, a company must specify the intended uses of a product in its new drug application to FDA. Once approved, the drug may not be marketed or promoted for so-called "off-label" uses – i.e., any use not specified in an application and approved by FDA. Pfizer promoted the sale of Bextra for several uses and dosages that the FDA specifically declined to approve due to safety concerns. The company will pay a criminal fine of $1.195 billion, the largest criminal fine ever imposed in the United States for any matter. Pharmacia & Upjohn will also forfeit $105 million, for a total criminal resolution of $1.3 billion.
In addition, Pfizer has agreed to pay $1 billion to resolve allegations under the civil False Claims Act that the company illegally promoted four drugs – Bextra; Geodon, an anti-psychotic drug; Zyvox, an antibiotic; and Lyrica, an anti-epileptic drug – and caused false claims to be submitted to government health care programs for uses that were not medically accepted indications and therefore not covered by those programs. The civil settlement also resolves allegations that Pfizer paid kickbacks to health care providers to induce them to prescribe these, as well as other, drugs. The federal share of the civil settlement is $668,514,830 and the state Medicaid share of the civil settlement is $331,485,170. This is the largest civil fraud settlement in history against a pharmaceutical company.
As part of the settlement, Pfizer also has agreed to enter into an expansive corporate integrity agreement with the Office of Inspector General of the Department of Health and Human Services. That agreement provides for procedures and reviews to be put in place to avoid and promptly detect conduct similar to that which gave rise to this matter.
Whistleblower lawsuits filed under the qui tam provisions of the False Claims Act that are pending in the District of Massachusetts, the Eastern District of Pennsylvania and the Eastern District of Kentucky triggered this investigation. As a part of today’s resolution, six whistleblowers will receive payments totaling more than $102 million from the federal share of the civil recovery.
The U.S. Attorney’s offices for the District of Massachusetts, the Eastern District of Pennsylvania, and the Eastern District of Kentucky, and the Civil Division of the Department of Justice handled these cases. The U.S. Attorney’s Office for the District of Massachusetts led the criminal investigation of Bextra. The investigation was conducted by the Office of Inspector General for the Department of Health and Human Services (HHS), the FBI, the Defense Criminal Investigative Service (DCIS), the Office of Criminal Investigations for the Food and Drug Administration (FDA), the Veterans’ Administration’s (VA) Office of Criminal Investigations, the Office of the Inspector General for the Office of Personnel Management (OPM), the Office of the Inspector General for the United States Postal Service (USPS), the National Association of Medicaid Fraud Control Units and the offices of various state Attorneys General.
"Today’s landmark settlement is an example of the Department of Justice’s ongoing and intensive efforts to protect the American public and recover funds for the federal treasury and the public from those who seek to earn a profit through fraud. It shows one of the many ways in which federal government, in partnership with its state and local allies, can help the American people at a time when budgets are tight and health care costs are increasing," said Associate Attorney General Tom Perrelli. "This settlement is a testament to the type of broad, coordinated effort among federal agencies and with our state and local partners that is at the core of the Department of Justice’s approach to law enforcement."
"This historic settlement will return nearly $1 billion to Medicare, Medicaid, and other government insurance programs, securing their future for the Americans who depend on these programs," said Kathleen Sebelius, Secretary of Department of Health and Human Services. "The Department of Health and Human Services will continue to seek opportunities to work with its government partners to prosecute fraud wherever we can find it. But we will also look for new ways to prevent fraud before it happens. Health care is too important to let a single dollar go to waste."
"Illegal conduct and fraud by pharmaceutical companies puts the public health at risk, corrupts medical decisions by health care providers, and costs the government billions of dollars," said Tony West, Assistant Attorney General for the Civil Division. "This civil settlement and plea agreement by Pfizer represent yet another example of what penalties will be faced when a pharmaceutical company puts profits ahead of patient welfare."
"The size and seriousness of this resolution, including the huge criminal fine of $1.3 billion, reflect the seriousness and scope of Pfizer’s crimes," said Mike Loucks, acting U.S. Attorney for the District of Massachusetts. "Pfizer violated the law over an extensive time period. Furthermore, at the very same time Pfizer was in our office negotiating and resolving the allegations of criminal conduct by its then newly acquired subsidiary, Warner-Lambert, Pfizer was itself in its other operations violating those very same laws. Today’s enormous fine demonstrates that such blatant and continued disregard of the law will not be tolerated."
"Although these types of investigations are often long and complicated and require many resources to achieve positive results, the FBI will not be deterred from continuing to ensure that pharmaceutical companies conduct business in a lawful manner," said Kevin Perkins, FBI Assistant Director, Criminal Investigative Division.
"This resolution protects the FDA in its vital mission of ensuring that drugs are safe and effective. When manufacturers undermine the FDA’s rules, they interfere with a doctor’s judgment and can put patient health at risk," commented Michael L. Levy, U.S. Attorney for the Eastern District of Pennsylvania. "The public trusts companies to market their drugs for uses that FDA has approved, and trusts that doctors are using independent judgment. Federal health dollars should only be spent on treatment decisions untainted by misinformation from manufacturers concerned with the bottom line."
"This settlement demonstrates the ongoing efforts to pursue violations of the False Claims Act and recover taxpayer dollars for the Medicare and Medicaid programs," noted Jim Zerhusen, U.S. Attorney for the Eastern District of Kentucky.
"This historic settlement emphasizes the government’s commitment to corporate and individual accountability and to transparency throughout the pharmaceutical industry," said Daniel R. Levinson, Inspector General of the United States Department of Health and Human Services. "The corporate integrity agreement requires senior Pfizer executives and board members to complete annual compliance certifications and opens Pfizer to more public scrutiny by requiring it to make detailed disclosures on its Web site. We expect this agreement to increase integrity in the marketing of pharmaceuticals."
"The off-label promotion of pharmaceutical drugs by Pfizer significantly impacted the integrity of TRICARE, the Department of Defense’s healthcare system," said Sharon Woods, Director, Defense Criminal Investigative Service. "This illegal activity increases patients’ costs, threatens their safety and negatively affects the delivery of healthcare services to the over nine million military members, retirees and their families who rely on this system. Today’s charges and settlement demonstrate the ongoing commitment of the Defense Criminal Investigative Service and its law enforcement partners to investigate and prosecute those that abuse the government’s healthcare programs at the expense of the taxpayers and patients."
"Federal employees deserve health care providers and suppliers, including drug manufacturers, that meet the highest standards of ethical and professional behavior," said Patrick E. McFarland, Inspector General of the U.S. Office of Personnel Management. "Today’s settlement reminds the pharmaceutical industry that it must observe those standards and reflects the commitment of federal law enforcement organizations to pursue improper and illegal conduct that places health care consumers at risk."
"Health care fraud has a significant financial impact on the Postal Service. This case alone impacted more than 10,000 postal employees on workers’ compensation who were treated with these drugs," said Joseph Finn, Special Agent in Charge for the Postal Service’s Office of Inspector General. "Last year the Postal Service paid more than $1 billion in workers’ compensation benefits to postal employees injured on the job."
Pharmacia & Upjohn Company has agreed to plead guilty to a felony violation of the Food, Drug and Cosmetic Act for misbranding Bextra with the intent to defraud or mislead. Bextra is an anti-inflammatory drug that Pfizer pulled from the market in 2005. Under the provisions of the Food, Drug and Cosmetic Act, a company must specify the intended uses of a product in its new drug application to FDA. Once approved, the drug may not be marketed or promoted for so-called "off-label" uses – i.e., any use not specified in an application and approved by FDA. Pfizer promoted the sale of Bextra for several uses and dosages that the FDA specifically declined to approve due to safety concerns. The company will pay a criminal fine of $1.195 billion, the largest criminal fine ever imposed in the United States for any matter. Pharmacia & Upjohn will also forfeit $105 million, for a total criminal resolution of $1.3 billion.
In addition, Pfizer has agreed to pay $1 billion to resolve allegations under the civil False Claims Act that the company illegally promoted four drugs – Bextra; Geodon, an anti-psychotic drug; Zyvox, an antibiotic; and Lyrica, an anti-epileptic drug – and caused false claims to be submitted to government health care programs for uses that were not medically accepted indications and therefore not covered by those programs. The civil settlement also resolves allegations that Pfizer paid kickbacks to health care providers to induce them to prescribe these, as well as other, drugs. The federal share of the civil settlement is $668,514,830 and the state Medicaid share of the civil settlement is $331,485,170. This is the largest civil fraud settlement in history against a pharmaceutical company.
As part of the settlement, Pfizer also has agreed to enter into an expansive corporate integrity agreement with the Office of Inspector General of the Department of Health and Human Services. That agreement provides for procedures and reviews to be put in place to avoid and promptly detect conduct similar to that which gave rise to this matter.
Whistleblower lawsuits filed under the qui tam provisions of the False Claims Act that are pending in the District of Massachusetts, the Eastern District of Pennsylvania and the Eastern District of Kentucky triggered this investigation. As a part of today’s resolution, six whistleblowers will receive payments totaling more than $102 million from the federal share of the civil recovery.
The U.S. Attorney’s offices for the District of Massachusetts, the Eastern District of Pennsylvania, and the Eastern District of Kentucky, and the Civil Division of the Department of Justice handled these cases. The U.S. Attorney’s Office for the District of Massachusetts led the criminal investigation of Bextra. The investigation was conducted by the Office of Inspector General for the Department of Health and Human Services (HHS), the FBI, the Defense Criminal Investigative Service (DCIS), the Office of Criminal Investigations for the Food and Drug Administration (FDA), the Veterans’ Administration’s (VA) Office of Criminal Investigations, the Office of the Inspector General for the Office of Personnel Management (OPM), the Office of the Inspector General for the United States Postal Service (USPS), the National Association of Medicaid Fraud Control Units and the offices of various state Attorneys General.
"Today’s landmark settlement is an example of the Department of Justice’s ongoing and intensive efforts to protect the American public and recover funds for the federal treasury and the public from those who seek to earn a profit through fraud. It shows one of the many ways in which federal government, in partnership with its state and local allies, can help the American people at a time when budgets are tight and health care costs are increasing," said Associate Attorney General Tom Perrelli. "This settlement is a testament to the type of broad, coordinated effort among federal agencies and with our state and local partners that is at the core of the Department of Justice’s approach to law enforcement."
"This historic settlement will return nearly $1 billion to Medicare, Medicaid, and other government insurance programs, securing their future for the Americans who depend on these programs," said Kathleen Sebelius, Secretary of Department of Health and Human Services. "The Department of Health and Human Services will continue to seek opportunities to work with its government partners to prosecute fraud wherever we can find it. But we will also look for new ways to prevent fraud before it happens. Health care is too important to let a single dollar go to waste."
"Illegal conduct and fraud by pharmaceutical companies puts the public health at risk, corrupts medical decisions by health care providers, and costs the government billions of dollars," said Tony West, Assistant Attorney General for the Civil Division. "This civil settlement and plea agreement by Pfizer represent yet another example of what penalties will be faced when a pharmaceutical company puts profits ahead of patient welfare."
"The size and seriousness of this resolution, including the huge criminal fine of $1.3 billion, reflect the seriousness and scope of Pfizer’s crimes," said Mike Loucks, acting U.S. Attorney for the District of Massachusetts. "Pfizer violated the law over an extensive time period. Furthermore, at the very same time Pfizer was in our office negotiating and resolving the allegations of criminal conduct by its then newly acquired subsidiary, Warner-Lambert, Pfizer was itself in its other operations violating those very same laws. Today’s enormous fine demonstrates that such blatant and continued disregard of the law will not be tolerated."
"Although these types of investigations are often long and complicated and require many resources to achieve positive results, the FBI will not be deterred from continuing to ensure that pharmaceutical companies conduct business in a lawful manner," said Kevin Perkins, FBI Assistant Director, Criminal Investigative Division.
"This resolution protects the FDA in its vital mission of ensuring that drugs are safe and effective. When manufacturers undermine the FDA’s rules, they interfere with a doctor’s judgment and can put patient health at risk," commented Michael L. Levy, U.S. Attorney for the Eastern District of Pennsylvania. "The public trusts companies to market their drugs for uses that FDA has approved, and trusts that doctors are using independent judgment. Federal health dollars should only be spent on treatment decisions untainted by misinformation from manufacturers concerned with the bottom line."
"This settlement demonstrates the ongoing efforts to pursue violations of the False Claims Act and recover taxpayer dollars for the Medicare and Medicaid programs," noted Jim Zerhusen, U.S. Attorney for the Eastern District of Kentucky.
"This historic settlement emphasizes the government’s commitment to corporate and individual accountability and to transparency throughout the pharmaceutical industry," said Daniel R. Levinson, Inspector General of the United States Department of Health and Human Services. "The corporate integrity agreement requires senior Pfizer executives and board members to complete annual compliance certifications and opens Pfizer to more public scrutiny by requiring it to make detailed disclosures on its Web site. We expect this agreement to increase integrity in the marketing of pharmaceuticals."
"The off-label promotion of pharmaceutical drugs by Pfizer significantly impacted the integrity of TRICARE, the Department of Defense’s healthcare system," said Sharon Woods, Director, Defense Criminal Investigative Service. "This illegal activity increases patients’ costs, threatens their safety and negatively affects the delivery of healthcare services to the over nine million military members, retirees and their families who rely on this system. Today’s charges and settlement demonstrate the ongoing commitment of the Defense Criminal Investigative Service and its law enforcement partners to investigate and prosecute those that abuse the government’s healthcare programs at the expense of the taxpayers and patients."
"Federal employees deserve health care providers and suppliers, including drug manufacturers, that meet the highest standards of ethical and professional behavior," said Patrick E. McFarland, Inspector General of the U.S. Office of Personnel Management. "Today’s settlement reminds the pharmaceutical industry that it must observe those standards and reflects the commitment of federal law enforcement organizations to pursue improper and illegal conduct that places health care consumers at risk."
"Health care fraud has a significant financial impact on the Postal Service. This case alone impacted more than 10,000 postal employees on workers’ compensation who were treated with these drugs," said Joseph Finn, Special Agent in Charge for the Postal Service’s Office of Inspector General. "Last year the Postal Service paid more than $1 billion in workers’ compensation benefits to postal employees injured on the job."
Pfizer Pays $2.3 Billion to Settle Marketing Case
By GARDINER HARRIS
NY Times
WASHINGTON — Top aides in the Obama administration announced a $2.3 billion settlement on Wednesday with the pharmaceutical giant Pfizer Inc. over the company’s illegal promotion of its now-withdrawn painkiller, Bextra.
It is the largest fine ever levied for fraud in the Medicare and Medicaid programs, and Obama administration officials — criticized by Republicans on Capitol Hill for failing to crack down on fraud in the government’s health programs — sought to highlight the case by having Health and Human Services Secretary Kathleen Sebelius make the announcement. The agreement also includes some promotional practices involving other Pfizer drugs — Zyvox, Geodon and Lyrica.
The settlement had been expected. Pfizer, which is acquiring a rival Wyeth, had reported in January that it had taken a $2.3 billion charge to resolve claims involving Bextra and other drugs.
Marketing fraud cases against pharmaceutical companies have become almost routine, with almost every major drug maker being accused of giving kickbacks to doctors or shortchanging the Medicaid program on prices. Prosecutors said that they have become so alarmed by the growing criminality in the industry that they have begun hiking fines into the billions of dollars and will soon start charging doctors individually as well.
Under the agreement with the Department of Justice, Pfizer will pay a $1.3 billion criminal penalty related to Bextra and $1 billion in civil fines related to a number of medicines. In addition, a Pfizer subsidiary, Pharmacia & Upjohn Company, will plead guilty to violating the Food, Drug, and Cosmetic Act for its promotion of Bextra.
In January, prosecutors announced that they would fine Eli Lilly $1.4 billion for its illegal marketing efforts on behalf of Zyprexa, an antipsychotic.
Although the fine amounts began to soar during the Bush administration, top administration officials rarely touted the cases or appeared during news conferences about them. The Zyprexa case was announced by federal prosecutors in Philadelphia.
Ms. Sebelius’s decision to make the Pfizer announcement in a news conference in Washington suggests that the political environment for the pharmaceutical industry has become more treacherous — despite the industry’s commitment to save the government $80 billion as part of efforts to change the health care system.
In addition, Pfizer has reached agreements with attorneys general in 42 states and the District of Columbia to settle state claims related to its promotional practices concerning Geodon. The company will pay $33 million to the settling states and will take a charge in that amount to third-quarter 2009 earnings.
NY Times
WASHINGTON — Top aides in the Obama administration announced a $2.3 billion settlement on Wednesday with the pharmaceutical giant Pfizer Inc. over the company’s illegal promotion of its now-withdrawn painkiller, Bextra.
It is the largest fine ever levied for fraud in the Medicare and Medicaid programs, and Obama administration officials — criticized by Republicans on Capitol Hill for failing to crack down on fraud in the government’s health programs — sought to highlight the case by having Health and Human Services Secretary Kathleen Sebelius make the announcement. The agreement also includes some promotional practices involving other Pfizer drugs — Zyvox, Geodon and Lyrica.
The settlement had been expected. Pfizer, which is acquiring a rival Wyeth, had reported in January that it had taken a $2.3 billion charge to resolve claims involving Bextra and other drugs.
Marketing fraud cases against pharmaceutical companies have become almost routine, with almost every major drug maker being accused of giving kickbacks to doctors or shortchanging the Medicaid program on prices. Prosecutors said that they have become so alarmed by the growing criminality in the industry that they have begun hiking fines into the billions of dollars and will soon start charging doctors individually as well.
Under the agreement with the Department of Justice, Pfizer will pay a $1.3 billion criminal penalty related to Bextra and $1 billion in civil fines related to a number of medicines. In addition, a Pfizer subsidiary, Pharmacia & Upjohn Company, will plead guilty to violating the Food, Drug, and Cosmetic Act for its promotion of Bextra.
In January, prosecutors announced that they would fine Eli Lilly $1.4 billion for its illegal marketing efforts on behalf of Zyprexa, an antipsychotic.
Although the fine amounts began to soar during the Bush administration, top administration officials rarely touted the cases or appeared during news conferences about them. The Zyprexa case was announced by federal prosecutors in Philadelphia.
Ms. Sebelius’s decision to make the Pfizer announcement in a news conference in Washington suggests that the political environment for the pharmaceutical industry has become more treacherous — despite the industry’s commitment to save the government $80 billion as part of efforts to change the health care system.
In addition, Pfizer has reached agreements with attorneys general in 42 states and the District of Columbia to settle state claims related to its promotional practices concerning Geodon. The company will pay $33 million to the settling states and will take a charge in that amount to third-quarter 2009 earnings.
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