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AIDS Treatment News
April 19, 1996

CONTENTS:

Crixivan(R) Price Break for Cash Customers: 
$97 Per Month Less, If You Ask

After extensive protest against the large markup on Merck's protease inhibitor (from $12 per day which is Merck's price, to the $16.50 per day retail price for cash customers), Stadtlanders Pharmacy has found a way to reduce the cash price from $16.50 to $13.27 (consistent with it contractual obligations to insurance companies and managed-care plans, which already get discounted prices). They will do this by honoring a discount card which has long been provided by another mail-order pharmacy, Community Prescription Service (CPS). The CPS card costs $18, and is honored by about 60% of pharmacies in the U.S., who give a negotiated below-retail price to card holders, not only for Crixivan.

Note: Due to a special temporary distribution program for indinavir (Crixivan), described in AIDS Treatment News #244, April 5, 1996, most patients can only order this drug through Stadtlanders.

It appears to be most convenient if you get the card in advance directly through CPS. For more information, or to order the discount card, call CPS at 800/842-0502. But you can also ask for the card when you call Stadtlanders for your monthly Crixivan prescription; they can order it for you from CPS and give you the discount immediately.

This program was announced on April 18, and largely negotiated the day before. It may take a few days or more for Stadtlanders' phone operators to be told about the program and trained in how to use it.

Note: The reason for this price irrationality is that there has to be a "retail" price substantially higher than the negotiated discount prices which large institutions pay.


Protease Inhibitors: 
Ritonavir and Saquinavir 
Combination Trial Recruiting 
-- Seven U.S., Canada Sites 
Including San Francisco

The first trial to combine protease inhibitors is now recruiting 120 volunteers in seven sites in the U.S. and Canada. This study is being conducted by Abbott Laboratories, Inc.

There is much interest in combining these two drugs, for several reasons -- but there are also potentially serious safety concerns. Saquinavir is quickly eliminated from the body, making it hard to get sufficient blood levels with the currently approved drug formulation; ritonavir, given with saquinavir, can produce increased and sustained levels of saquinavir because it slows the process used by the body to eliminate saquinavir. Also, the drugs have very different resistance patterns, which may work together well to slow the development of viral resistance to the combination.

But this combination must be tested very carefully. Correct dosing must be used when combining these drugs -- and the doses are not yet known. Blood levels of saquinavir become higher than previously achieved, and the safety of saquinavir at these blood levels is unknown. In addition, if doses are too low, viral resistance could develop. To help avoid these problems, blood levels will be measured in this trial, using a test which is not commercially available.

To be eligible, you must be at least 12 years old, have a CD4 count of 100 to 500, have never taken any protease inhibitor, have no acute opportunistic infection nor inflammation of the pancreas, and not be taking any medication contraindicated with ritonavir. You can be using other approved antiretrovirals (AZT, etc.), but will have to stop them two weeks before beginning treatment in this trial.

For more information about these trials, call Mabrey Whigham at the International Association of Physicians in AIDS Care, 312/419-7295. Or for the San Francisco trial, you could call the HIV Institute at Davies Medical Center, 415/565-6222. We could not determine the other cities before going to press.


Protease Inhibitors: 
Background Information

One of the best information sources on protease inhibitors continues to be the National AIDS Treatment Advocacy Project (NATAP). You can obtain its written report, get the most current information from its Web site, or obtain videotapes of two major community meetings which NATAP has held so far, in New York (January 26) and Los Angeles (April 13).
  • To obtain HIV PROTEASE INHIBITOR REPORT (Second Edition- 3/96), by Henry E. Chang and Jules Levin, contact NATAP, 72 Orange Street, #3C, Brooklyn, NY 11201, phone 718/624-8541, fax 718/624-8399. Please do not phone or fax late at night.
  • If you can use the World Wide Web, you can get additional information at http://www.aidsnyc.org/natap.
  • The entire 4-hour Los Angeles symposium is available on videotape -- $35 for individuals, $100 for professionals (doctors, hospitals, corporations, etc.), free or sliding scale for individuals who cannot afford to pay. You can order it from NATAP at the above address.

Los Angeles Meeting

About 700 people -- apparently a record for any AIDS medical meeting in Los Angeles -- filled the Paramount Pictures Theater on a Saturday afternoon, April 13, for "Protease Inhibitors: Current and Future Use," a free educational forum organized by Jules Levin of NATAP, along with over 15 Los Angeles AIDS organizations. The theater was still full three hours after the program started.

Perhaps the most important theme of the Los Angeles meeting was the need to follow medical advice and use these drugs properly. "Drug holidays," arbitrary dose reductions, and other misuse create windows of opportunity which can help the virus become resistant to the drugs. Once resistance develops, it is probably permanent, and one or more of the protease inhibitors will be less valuable to the patient in the future.

Note that some protease inhibitors must be taken on a full stomach, and others on an empty stomach, to be absorbed effectively. Physicians can give instructions on what is and what is not acceptable.

For persons beginning treatment with the Abbott protease inhibitor ritonavir (Norvir(TM)), Abbott is recommending a dosage ramp-up approach, in which slightly lower doses may be used for the first few days. This dose adjustment may help the body adapt to ritonavir by gradually introducing the drug into the blood. It may reduce unpleasant side effects which some (though not all) patients experience, especially during the first two weeks. Abbott does not expect this approach to increase drug resistance.

It is essential to follow medical advice about not combining the Abbott protease inhibitor with many other common drugs. Some of these drugs can cause life-threatening reactions if combined with ritonavir.

There are fewer side effects and drug interaction problems with the other two approved protease inhibitors, indinavir (Crixivan) and saquinavir (Invirase(TM)). But interaction and other safety precautions must be followed with these drugs too.

Meeting Organizers Note

Persons organizing AIDS meetings should note some of the factors which led to the large attendance of the protease inhibitor symposium in Los Angeles, a city where people are unlikely to come to AIDS meetings. (1) The topic was urgently important, as many people are starting these drugs and need information. (2) The symposium had very good support from local AIDS organizations, some of which mailed the flyer to their clients. (3) Volunteers carried flyers to HIV medical practices and clinics, coffeehouses and bookstores, and other appropriate locations. (4) Meeting organizer Jules Levin came to Los Angeles several days in advance to work full time on the arrangements.


Delavirdine Available 
on Expanded Access

Persons with a CD4 count of 300 or less who are failing other therapy may qualify for an open-label program to use the experimental antiretroviral delavirdine in combination with at least one other antiretroviral.

To be eligible, patients must not be hospitalized, or have "an acute, serious, life-threatening condition," or be treated concurrently with rifampin, rifabutin, astemizole, loratidine, or terfenidine. Patients must not have hemoglobin less than 8.0, neutrophils less than 600, platelets less than 25,000, or creatinine greater than 3.0. There are some additional entry criteria.

Your physician can register you for the program by calling 800/779-0070. Some paperwork will be required, and possibly local IRB approval. This program has already been approved by a national IRB.

For more information, persons in the U.S. and Canada can call 800/432-4702 or 800/779-0070.


Sinusitis: Helpful Background, 
Treatment Article

A useful background article on sinusitis was published in the March 1996 issue of BETA (BULLETIN OF EXPERIMENTAL TREATMENT FOR AIDS), a treatment newsletter published by the San Francisco AIDS Foundation. "Sinusitis," by Leslie Hanna of the Foundation, looks at causes, symptoms and diagnosis, and various different antibiotic and other treatments -- including acupuncture, herbal treatments and holistic interventions.

San Francisco residents may pick up a free copy of BETA at the San Francisco AIDS Foundation, 10 UN Plaza, at the Client Services Waiting Room on the 2nd floor. Others may call BETA at 415/487-8060 to get a copy or a reprint.

Subscriptions to BETA cost $75 (institutional rate $165), and can be ordered by calling 800/959-1059.


Chinese Medicine: 
Qigong Exercise Tape Available

For several years Emilio Gonzalez and George Wedemeyer have been leading classes in Qigong, a form of exercise used in traditional Chinese medicine. The classes, for people with HIV or other chronic diseases, request a nominal donation of $1. Now the instructors, both long-term AIDS survivors, have produced a four-week Qigong class on videotape, with help from video professionals who volunteered for this project. All proceeds from the sale of the tape will support direct client services at the Immune Enhancement Project (IEP), an acupuncture clinic in San Francisco. (For an interview with Tom Sinclair, L.Ac., executive director of the Immune Enhancement Project, see AIDS Treatment News #230 , September 1, 1995.)

The two-tape set, with four lessons totaling two and a half hours, can be ordered for $59.95 from the Immune Enhancement Project, 3450 16th St., San Francisco, California 94114, 800/835-6555 or 415/252-8711, fax 415/252-8710.

For more information about the San Francisco classes, call George Wedemeyer, 415/975-4561 or Emilio Gonzalez, 415/255- 0265. Or check the IEP home page on the World Wide Web, http://www.creative.net/~iep -- which also includes a form for ordering the tape by fax.


rGP-160 Treatment Vaccine (VaxSyn): 
Canadian Study Finds No Benefit

A multi-center trial in Canada, which gave either recombinant GP-160 or placebo to 278 volunteers with HIV during a three- year study, found "no clinical benefit from this product nor any usefulness in maintaining immune competence," according to Chris Tsoukas, M.D., of Montreal General Hospital. Dr. Tsoukas noted that these results do not apply to preventive vaccine trials.

The Canadian study was completed in November 1995, but the results were not announced until a similar U.S. study was completed in March.

Only a brief announcement of the negative finding has been made at this time. Detailed results may be available in a few weeks.

Comment

This negative result illustrates the need for research in HIV pathogenesis, and particularly in the correlates of immunity. It is easy to produce an antibody response, or other kinds of immune response to HIV. What is much harder is to know what kinds of immune response are protective.

While difficult, this problem is not impossible. Studies of long-term nonprogressors (who have HIV but do not get sick), and of persons who have been repeatedly exposed to HIV and remained uninfected, may help to determine what kinds of immunity are effective in preventing or controlling infection.


FDA Reform in Congress: 
Interview with Peter Barton Hutt

by John S. James
Legislation to change the U.S. Food and Drug Administration has now been introduced in both houses of Congress. This legislation might become law, and interested parties need to make themselves heard now, as Congress must act quickly on these bills, or it will be too late for this year. Those who are not aware of the issues involved could miss the chance to have a say in decisions affecting them.

For one view on these issues, AIDS Treatment News interviewed Peter Barton Hutt, who is widely recognized as one of the world's leading experts on FDA law. Mr. Hutt has practiced regulatory law for the past 35 years, and served as general counsel of the FDA between 1971 and 1975. He is now in private practice at the Washington D.C. law firm of Covington and Burling, and also teaches a course in food and drug law at Harvard Law School.

We told Mr. Hutt that we were especially interested in the earlier stages of the drug development process, as well as in the current legislation.

AIDS Treatment News: Some people are saying that the rapid approval of protease inhibitors shows that FDA reform legislation is not needed, that any problems have already been fixed. What else should these people be aware of?

Hutt: The rapid approval of a number of new drugs shows that where FDA wishes to do so, it can place its resources and can improve the system. The difficulty is that those cases represent ad hoc decisions under a great deal of pressure at one particular point in time, and do not represent a systematic change in FDA procedures and policies. One cannot conclude that these improvements will apply for a longer time to a wider group of therapies.

The drug approval process cannot be viewed in isolation. It is part of an extraordinary lengthy discovery, research, and development process that now takes more than a decade. Only 20 years ago, the process from drug discovery to approval averaged approximately six to at most eight years. Today it is in the area of 15 to 16 years. The time required has roughly doubled during the last two decades.

What has happened is that the FDA has become more stringent overall in its requirements. While the time for APPROVAL has remained the same or diminished slightly, the time for research and development has escalated dramatically, making it take even longer for important new products to reach the marketplace. Therefore, in looking at legislation, one must focus on all aspects of this process, not only on the final decision of approval or disapproval.

ATN: Where in the earlier phases do you think major time savings can and should be made?

Hutt: They must be made in every stage. The first stage is preclinical testing. FDA has requirements that must be met before any drug can be put into a human. These have been relatively stringent and relatively inflexible. If they are made less stringent and more flexible, human trials could start more rapidly.

Second, one must look at the requirements FDA has imposed for submission of an IND application. [Note: An IND -- Investigational New Drug -- application must be approved by the FDA before a new drug can be tested in humans.] If you compare the size and content of an IND in the United States and in Europe, you will see that the one in the United States can be six or eight feet thick, and the one in Europe is six or eight inches. That difference represents an enormous investment of time, resources, and of course money. In Europe you can investigate more drugs than in the United States, because the investment required is less.

Third, when you look at the requirements for monitoring and record keeping, and adverse reaction reporting, in Europe vs. the United States, you understand why more and more clinical trials are being conducted abroad. You can do much more for less money, more quickly and more efficiently, abroad than you can in the United States. The consequence is that some investigational drugs which are available abroad cannot be used for any form of expanded access or compassionate use in this country.

ATN: The cost of new AIDS drugs is now a major issue. Could we reduce drug prices by cutting the cost of development?

Hutt: Time is money. The amount of resources needed to investigate and ultimately bring to approval a new drug depends on time, and also on the complexity of the requirements imposed. Regulatory requirements therefore directly decide the ultimate price of a drug.

ATN: Someone described the current "Good Laboratory Practice" regulations as 40 tons of cure imposed because of isolated instances of abuse.

Hutt: One company submitted fraudulent data on its testing of pesticides and other products. As a result, FDA imposed, in the late 1970s, stringent Good Laboratory Practice record keeping requirements that are enormously costly and burdensome.

Every bit of this contributes to cost and time. The difficulty is that, if you take any one of these issues in isolation, you can find some justification for it. In isolation, you can say, "That only costs so much more." But if you put them all together -- and consider that they have been added one on top of the other for the last 40 years -- you begin to understand the enormous impact.

ATN: How do the bills in Congress now address these problems? [Note: The bills referred to in the following discussion are S. 1477, introduced by Senator Nancy Kassebaum, Republican, Kansas, on December 13, 1995, and H.R. 3199, introduced in the House by Congressman Richard Burr, Republican, North Carolina, on March 29, 1996.]

Hutt: These bills are remarkably close in philosophy and intent. They are written with different words and phrases, but that should not be interpreted as meaning a fundamentally or structurally different approach. They are very similar.

ATN: We reported to our readers when a draft of the Kassebaum bill became available (see AIDS Treatment News #235, November 17, 1995) that this bill focuses on procedures to hold the FDA accountable for its performance, rather than on mandating or micromanaging specific decisions.

Hutt: The same concept occurs in the House bill. That is why I said they are similar in concept. Both bills realized that you cannot focus on just one part of the total discovery, research, development, and approval process. You have to deal with every aspect of that or you will not make a difference.

Each bill has its strength and weaknesses. Let me mention one difference which is important, and may be misunderstood.

The Senate bill contains a provision, a strongly worded statement of philosophy, which says that any patient, through a physician, has the right to request an investigational drug for expanded access treatment use, and any company has the right to provide that. The company does not have an obligation to provide it, but they have the right to do so. That statement does not occur in the House bill, but the House bill clearly provides, without saying it, that the same is true.

My personal preference would be to include this explicitly in the legislation. But it is erroneous to think that the House does not agree with expanded access because it did not include this specific language. I would certainly support an explicit provision of that kind, which gives a flavor, tone, or mandate that otherwise might not be clearly understood.

ATN: But it does not create a new legal right?

Hutt: It is legally unenforceable in both bills, but it is nonetheless a very powerful statement of intent.

ATN: But you think that patient advocates might want to make it clear to Congress that they want the Kassebaum version to prevail in the final legislation?

Hutt: Yes. I believe interested people should make clear to the House that they consider immediately incorporating it into the next version of the bill.

ATN: And they could copy the language right out of the Kassebaum bill?

Hutt: Yes. The language in the Kassebaum bill to my knowledge has not been substantially opposed by anyone -- not by patient groups, not by the industry, not by consumer advocates, not by anyone. It may have been omitted from the House bill only because nobody lobbied the House on it.

Hutt: There is another important provision in the Senate bill that your readers should be aware of, and come to their own decision. Under current FDA regulations, for a drug treatment IND and for all medical devices, a company is permitted to charge for an investigational product. They can charge for the manufacture of the drug, for the cost of research and development, and for the cost of handling. Under the Senate bill, the cost of research and development was deleted.

The first question is, what does that mean? Will the FDA have to delete the cost of research and development from the treatment IND and medical device regulations? I do not believe that is what is intended, but the meaning is quite unclear. The second question is why was that provision deleted, who deleted it, and what was the intent of the Committee? That is unclear to me as well.

If in fact it means that companies would be completely prohibited from taking into account their research and development costs in charging for investigational products, it seems to me highly probably that far fewer companies would be willing to make investigational products available. They would be lucky to break even. Considering the time and effort it takes them to provide expanded access, it would undoubtedly not be worth their effort. In my judgment, this change would substantially reduce the number of investigational products available for expanded assess. People should consider this issue, and whatever their views are, make them known to both the Senate and the House. There is no comparable provision in the House bill.

ATN: What is the timetable for this FDA legislation?

Hutt: The timetable in Congress is tight. There are relatively few legislative days left in Congress this session. Senator Dole, on the campaign trail, did commit to bring this bill to the floor in the Senate, so it is likely that will happen.

ATN: Is Kennedy likely to oppose the bill, or not?

Hutt: The position of Senator Kennedy remains unclear. He voted against the bill in the Senate markup, but three Democrats voted for it. There are attempts to achieve compromise to make it less likely that he will oppose it. It is entirely uncertain what his ultimate position will be.

ATN: Is Kennedy concerned about allowing pharmaceutical companies to talk about off label uses of drugs?

Hutt: That provision was deleted from the Senate bill in the markup, because the Committee could not reach a consensus on exactly what it should say. There are efforts now to reach a compromise and put that provision back into the bill.

ATN: What are Kennedy's main objections at this point?

Hutt: That is a very long story. It appears that every time one of his objections is met, he comes up with a new objection on a different provision. There is some concern that there is an endless list that would gut the entire legislation if it were met.

ATN: Do you think the FDA wants to conduct a war of attrition against the bill through Senator Kennedy?

Hutt: In one syllable, yes. This is not a surprising strategy. The FDA is totally opposed to the entire legislation. There is nothing in the bill that is acceptable to FDA. It will do whatever it can to delay the bill or defeat it.

ATN: What can individuals and organizations do to get their views heard and considered on these issues, at this late time?

Hutt: People should work through their organized groups, which are singularly the most effective way of making their views known, as well as getting in touch with their own personal representatives in the Senate and the House. Working through organized groups that are in Washington, and can monitor the progress and the changes that are made, is always the most effective way to proceed.


FDA Reform in Congress: 
FDA's Concerns

by John S. James
Perhaps the best case against major elements of the FDA reform legislation now being considered by Congress is the February 21, 1996 testimony of FDA Commissioner David A. Kessler, M.D., before the Senate Committee on Labor and Human Resources -- chaired by Senator Nancy Kassebaum, Republican, Kansas, who introduced S. 1477. It is impossible to meaningfully summarize this statement, which is 48 pages double spaced plus 19 pages of attachments. But we want to give our readers a sense of some of the concerns. (Note: Kessler's testimony addressed only S. 1477; H.R. 3199 had not been introduced yet.)

Dr. Kessler urged Congress to consider the progress in rapid drug reviews and other areas that has been made in the past several years. "If we are to achieve our shared goals of improving the Agency's ability to protect and promote the public health, we must base our work on FDA's current performance. Unfortunately, too many of our critics justify the call for 'reform' based on how the FDA did its job in the 1980s or earlier. They have missed the substantial progress that the dedicated doctors, nurses, engineers, chemists, microbiologists, biostatisticians, nutritionists and others at the FDA have achieved over the past several years. They would have us ignore the important lessons that we have learned about the kinds of change that will result in getting safe and effective drugs and devices to the market more quickly. Those who fail to recognize the Agency's performance and achievements threaten -- intentionally or not -- to undermine the real progress the Agency has made. Undermining progress in critical public health and consumer protection is not 'reform.'"

Dr. Kessler pointed out that according to a study by the General Accounting Office (GAO), the average time for approval of new drug applications was 33 months for applications submitted in 1987, but reduced to 19 months for those submitted in 1992. This, he noted, was largely due to user fees for prescription drug approvals -- a system created by Congress in 1992, with the approval of the pharmaceutical industry. Under this system, companies pay to have their applications processed by the FDA -- which uses the money to increase staff and other resources to get the applications handled more quickly. This system included performance goals for the FDA, which has already met the 1997 goal for reduced review time, three years ahead of schedule.

Kessler cited extensive comparisons between drug approval times in the U.S., the UK, Germany, and Japan -- making a strong case that the U.S. now has the fastest drug approvals of the four.

But Dr. Kessler was concerned about the requirement of S. 1477 that by July 1998 the FDA would review all drug approval applications within 180 days, and priority drugs within 120 days. "I do not believe that the Agency could meet the product review times set forth in S. 1477, with existing resources, without compromising existing public health protection...

"What does it take to review an application within four to six months? First, it takes an excellent application. With only four to six months there would be little opportunity to obtain clarifications or additional information from the sponsor. Although every application could be reviewed exactly as it is submitted, very few applications are so complete and accurately presented as to be approvable without further discussion with the sponsor. Second, it requires having the necessary review staff, including all the various disciplines, ready to work on the application the day it comes in the door. That means other work needs to be put on hold. Third, it means companies will need to be fully ready to manufacture the drug... Fourth, the shortened review times will compromise the effectiveness of advisory committees...

"Under the S. 1477 timeframes, the Agency also would be required to limit its involvement in the production and post- approval areas... In fiscal 1995, there were 251 product recalls."

"Shortening the review times also will adversely impact Agency programs that are NOT related to drugs or other product approval process, such as the safety of the blood supply, food safety and tampering, and mammography quality. Our efforts to protect the public from unsafe imported products -- whether it is botulism-contaminated mushrooms or hepatitis-contaminated human tissue, will have to be curtailed. It will also severely curtail our ability to respond appropriately to emerging public health threats, crises, or even to new areas where a little work would have a large payoff."

Kessler outlined many other concerns:

"There are several sections of the bill that would establish new and lower product approval standards. For example, Section 407 would establish a new process for approving new uses of existing drugs that would completely bypass the drug approval process. It would establish a procedure for recognizing new uses based on medical practice... This provision moves us away from the accepted scientific standard of evidence back toward evidence based solely on anecdotal experience..."

"We are also concerned that the bill would eliminate FDA's role in assuring that modifications made to a product do not adversely affect its safety and effectiveness. Under the bill, unless the manufacturer's own data show that safety and effectiveness were to diminish, FDA could not require data on the modified product (Sections 702 and 707). Yet we know that such modifications can carry initially unrecognized risk..."

"We are equally concerned that the bill would remove even the basic assurance that most new devices will be well made. Under Section 702 a company, even one with known manufacturing problems directly relevant to its new device, would have to be given marketing approval even though the Agency has evidence the firm is unable to produce a quality product..."

"There are a number of provisions throughout the bill which would allow companies to market products without FDA approval, if the Agency fails to meet review deadlines..."

"The bill's requirement for third party review is equally troubling... FDA's scientists and experts are charged with exercising independent and unbiased judgment. They comply with stringent financial disclosure and conflict of interest requirements designed to protect the decision-making process against bias. It is not clear whether, and how, this independence can be maintained with private sector review organizations...

"The substitution of judgment also extends to the manufacturing area. When a contractor has given a manufacturer good marks for its production process, FDA is prohibited from inspecting the plant for two years unless the Agency learns through other means that there is something seriously wrong at the plant."

Other concerns involve expanded access -- now available through FDA regulations, which would be legislated instead, beyond the FDA's control:

"Unfortunately, S. 1477 (Section 202) would permit drug and device companies to side-step completely FDA's approval process and go into the manufacture, promotion, and sales of a product for any serious disease or condition without FDA approval. Under S. 1477's provisions, expanded access protocols could be given for any product that diagnoses, monitors, or treats a serious disease or condition, so long as other therapy is not 'comparable or satisfactory.'

"In addition, S. 1477 would permit the manufacturer to widely promote the availability of the expanded-access protocol (Section 202). Unlike FDA's current system for cost recovery under a treatment IND, there is no requirement in the bill that adequate enrollment be obtained for clinical trials that are designed to determine the safety and effectiveness of the product, and that the manufacturer pursue marketing approval with due diligence. In short, the patient would have to pay full price for an experimental product, and the company would be under no obligation to ever find out its true value. Coupled with the provision for cost recovery, promotion of the availability of experimental treatments would create a climate where the unscrupulous could sell untested hope with scant risk of being found out and only weak sanctions if they were. The 1995 Health and Human Services Inspector General's review of commercialization of unapproved medical devices shows this is not just a theoretical risk but a predatory business practice hard to control even with today's stronger law."

Off Label Drug Information

Major controversy exists about whether pharmaceutical companies should be allowed to promote "off label" uses of approved drugs -- that is, uses which have not specifically been approved by the FDA. The FDA realizes that off label drug uses can be appropriate and beneficial. But at present, a pharmaceutical salesperson cannot give a physician a peer- reviewed journal article about an unapproved use of the company's product, unless the physician asks for it.

Kessler did not address this issue, but left it to William B. Schultz, Deputy Commissioner for Policy, to present the FDA's position to the Senate Committee on Labor and Human Resources, on February 22, 1996. Schultz described a number of cases where allowing companies to promote off label uses would have led to serious harm.

We have not seen a similarly detailed case in favor of changing the current law. Such a document is needed, because this issue requires a judgment call. The examples cited by Schultz must be balanced against the damage caused by poorly informed physicians who do not read the literature or who find it safer for their careers to avoid initiative, and provide poor treatment to patients when better treatment is possible.

Schultz also described major FDA initiatives to reverse certain problems at the FDA in the past, and make it much easier for companies to get new indications onto the label. He noted that many off label uses could be approved with no new clinical trials, if companies would just copy existing data and submit them to the FDA. And the FDA is now working with leading physicians to identify the most important off label uses, in order to work with companies to get them approved.

Comment

Our goal in reporting the controversy about Congressionally- mandated FDA reform has been to expose our readers to leading advocates of both sides, and to the complexity of the issue. Those who work seriously in this area will need to study and listen to differing views. So far the custom has been to hear one side, and demonize the other.

The remarkably articulate and compelling arguments on both sides are only a beginning to understanding in this area. On closer look, both leave much to be desired. Hutt addresses easy issues of the current legislation. Kessler addresses hard ones, but questions remain.

For example, it could be argued that a "climate where the unscrupulous could sell untested hope" might ultimately save many more lives than the climate we have. For excluding "untested hope" has also largely excluded all contributions except from big business -- shutting out small companies, which are often the most creative, but which have to sell out to the big ones. (It is no accident that the driving force behind the current FDA-reform legislation is the medical- device industry, largely consisting of entrepreneurial companies far smaller than the huge corporations of the pharmaceutical industry.)

And also largely excluded is every medical tradition on Earth except for one -- the one which has developed only in the last several decades but has used its money to dominate Western institutions, especially in the U.S. This dominant tradition is increasingly based on formal evidence -- perhaps a major advantage -- but also it is notably crude, inefficient, narrow, and cruel in its methods of gaining knowledge. A better public policy might be to open the door somewhat wider, trusting more in the judgment of patients and physicians, judgment which of course includes formal evidence when available, but also includes other evidence not formalized yet. Yes, quacks will use the opening; but nothing eliminates quackery faster than treatments that really work. And it is preposterous to think that the best way to find treatments that work is to eliminate all of the human race except for the narrowest elites from any real role in medical development.

The most central issue, we believe -- beyond anything Congress does this year -- is how to make medical research and drug development work better. We fear that neither side in the politically charged debate has a useful answer. For decades, an FDA controlled by Democrats in Congress piled rule upon rule in the name of public safety, oblivious both to financial costs, and to the human costs of research stagnation. Now Republicans control Congress, and industry believes its day is here, and wants its reward. Both ideologies are a disservice to the public.

Perhaps the best we can hope for immediately is what has already been happening so far -- no new law, but the FDA so afraid of one that it does more than seemed possible to improve itself from within.

We believe that the key bottleneck in medical research is the difficulty of obtaining the first credible data in human testing of a new idea or approach. Senator Kassebaum's office chose NOT to address this issue in S. 1477 -- probably because the most visible proposal for doing so (letting institutional review boards bypass the FDA and approve human trials) clearly has drawbacks. No one knows how to balance safety and progress at the edge of creativity and the unknown. Perhaps there is no systematic way.

The current debate has been productive in stimulating FDA reform. It could be equally valuable if it shakes official Washington out of its traditional ignorance and disinterest in the obstacles to medical progress, and the opportunities to do better.

For More Information

  • Anyone can get current copies of this (and other) current Federal legislation through the World Wide Web, at address http://thomas.loc.gov/. Search for bill numbers s1477 and hr3199. There is no charge for using this service, which is provided by the Library of Congress.
  • The text of the testimony by Dr. Kessler and Mr. Schultz is available from the FDA Office of AIDS and Special Health Issues, 301/443-0104, fax 301/443-4555. On the World Wide Web, Dr. Kessler's talk is at http://www.fda.gov/ola/nktest.html. Also note the FDA home page, http://www.fda.gov.
  • The Log Cabin Republicans, a gay political organization, is supportive of both S. 1477 and H.R. 3199; their views are often close to those of Peter Hutt. They can be reached at 202/347-5306.
  • Most AIDS organizations which have a position are opposed to both bills. One source of information on the opposition is the Patients' Coalition; call Derek Link 212/337-3502. This association of health groups has many concerns. Link sees the bills primarily as privatization -- allowing private companies to do inspection and other work now done by FDA staff.
  • AIDS Action Council is working on this issue and is opposing both the bills. Press can contact Joe Zuniga 202/986-1300, x3042. Others can contact Scott Sanders at the American Foundation for AIDS Research, 202/331-8600.


Vancouver Conference: 
Make Travel Plans Now. 
Focus, Program, 
and Satellite Meetings

The program of the XI International Conference on AIDS (Vancouver, July 7-12, 1996) has been built around the abstracts submitted. Since the abstract deadline was February 1, and it took time to review and categorize the submissions, the major scientific issues which the conference will address are only now coming into view. Some of the areas which will receive most attention are:
  • Use of combination therapies with protease inhibitors;
  • Immunomodulators and malignancies;
  • Ethics and methodology of clinical trials;
  • Complementary therapies;
  • Management of HIV infection in children;
  • Resistance to antiretroviral drugs;
  • The HIV life cycle;
  • Viral pathogenesis;
  • New research in preventive vaccines;
  • Natural history and determinants of long-term non- progression;
  • Prevention of mother-to-child transmission;
  • Sexually transmitted disease prevention to reduce HIV infection;
  • Needle-exchange programs;
  • Female-controlled methods to prevent HIV transmission;
  • HIV and human rights;
  • Community mobilization;
  • Papers which seek to draw together activists, people living with HIV, and researchers around common interests.

A record number of abstracts -- 5,626 -- were submitted to this conference; this is more than for any other conference except Berlin, which allowed individuals to be presenting author for more than one abstract. About 90% of the Vancouver abstracts were accepted.

Plenary Program

The plenary program -- the talks and debates addressed to everyone at the conference -- is now as follows:

  • Monday July 8: Antiviral Therapy and Viral Load; HIV Genetic Diversity; The Epidemic of HIV among Young Gay Men; and a debate on whether the prohibition of addictive drugs can make a significant contribution to HIV prevention and control.
  • Tuesday July 9: Empowerment, Community Mobilization, and Social Change in the Face of AIDS; Perinatal Transmission; Female-Controlled Methods; and a debate on vaccines, whether more fundamental science is needed before large phase III vaccine trials.
  • Wednesday July 10: Molecular Biology and Drug Development; Continuum of Care in Resource Poor Settings; HIV and Development; and a debate, topic not yet set.
  • Thursday July 11: Positive Developments in Interventions; The Impact of HIV on Families and Children; HIV Viral Dynamics; and a debate on the relative contribution of viral factors vs. host factors in pathogenesis.

Travel, Media Arrangements

It is important to make travel reservations now, due to limited space in hotels and in flights into Vancouver.

Media persons must be accredited to cover the conference, and are strongly urged to take care of that now, due to limited hotels in Vancouver.

Contact Greg Hamara (see Contact Information, below).

Skills Building Meetings, July 8-11 Afternoons

"Managers, trainers, programmers, volunteers, and clinicians from developing countries are encouraged to participate with professional facilitators and experienced community based practitioners. The workshops will examine analytical tools, low cost technology and the experience of participants to find new personal and group resources for dealing with challenges of community based organizations."

Topics include assessing community needs, interactive training techniques, managing nutrition in the face of poverty, CD4 testing alternatives, writing a funding proposal, and many others.

For more information, contact Peter Gillies, Skills Building Coordinator, fax 604/668-3242, email pgillies@hivnet.ubc.ca, or wag@web.ca.

Community Forum 96, July 5-6

"Community Forum 96 is an international gathering of persons living with HIV/AIDS and community organization workers that will precede the XI International Conference on AIDS. Over a period of two days, this working meeting will bring together 500 persons -- 100 from each of the five regions of the world..."

For more information, contact the Community Liaison Department of the Conference Secretariat; see contact information below.

Satellite Meetings

Organizations and companies have scheduled the following satellite programs. Because of limited space, we have only listed the date, the sponsoring organization, and the title of the meeting, to help people plan their schedule and make travel arrangements. Time and place of these meetings, as well as contact persons and phone/fax numbers, are usually available from the conference site on the World Wide Web, http://www.interchg.ubc.ca/aids11/AIDS96.html.

Friday July 5

  • The AIDS Control and Prevention (AIDSCAP) Project of Family Health International and the Francois-Xavier Bagnoud Center for Health and Human Rights of the Harvard School of Public Health. Status & Trends of the Global HIV/AIDS Pandemic (continues July 6).
  • Global AIDS Information Network. 1996 Biennial Meeting.
  • National Institute of Mental Health. Role of Families in Preventing and Adapting to HIV/AIDS (continues July 6 and 7).

Saturday July 6

  • Canadian Association of Nurses in AIDS Care. Nursing: Sustaining the Circle of Life.
  • AIDSCAP/Family Health International. Men, Women and AIDS: A Dialog.
  • American Medical Association. AIDS Media Briefing.
  • International Christian AIDS Network. A Faith Response to HIV/AIDS (continues July 7).
  • Health Canada, U.S. Centers for Disease Control and Prevention, U.S. National Institutes of Health, The Joint United Nations Program on HIV/AIDS, and Canadian Public Health Association. HIV Prevention Works / La Prevention du VIH, ca marche / La Prevencion del VIH da resultados.
  • European Commission. The European Communities' HIV/AIDS Program for Developing Countries Directorate-General for Development.
  • Janssen-Cilag, Opportunistic Fungal Infections in HIV/AIDS: Emerging Challenges and a New Solution.

Sunday July 7 - Friday July 12

Many additional satellite meetings could not be listed here due to lack of space; we will publish them in our next issue. We included the pre-conference meetings now because they are most likely to affect travel plans. The later satellite meetings occur on the days of the conference itself.

Contact Information

Conference Secretariat, XI International Conference on AIDS, 11th floor, 1090 West Pender, Vancouver, British Columbia, Canada V6E 2N7; phone 800/780-AIDS, or 604/668-3225; fax 604/668-3242;

email aids96@hivnet.ubc.ca;

Web http://www.interchg.ubc.ca/aids11/AIDS96.html.




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