American Autoimmune Related Diseases Association, Inc.

Position Paper

A Greater Need for Patient Voice and Choice

I. The Meaning of “Patient Voice and Choice”?

Ongoing changes in the social, political and economic environment in the US have highlighted the increased need for patients to become even more deeply involved in key decision-making processes which have the potential to adversely impact their overall health, quality of life, and general well-being. As Congress and the FDA continue to tighten safety requirements for pharmaceuticals and, in the process, remove either existing or potential therapies from the market or delay the entry or re-entry of others, patients, as the ultimate consumers of these therapies, need to provide a counterbalancing force to critical safety assessments provided by non-patient consumer groups and the legal community. Patients need to continue to voice the paradigm that every therapy has a risk-to-benefit ratio which will vary by patient categories and even within those categories by individual patients. Just as the generalization cannot be made that no one drug will be effective for everyone, neither can it be said that a drug will have the same safety issues in all treated individuals.

For patients with autoimmune disease, this presents a critical issue as few good drugs exist to treat their conditions. The result is that autoimmune patients are often treated with a plethora of available therapies to treat both disease progression and the symptoms of the disease, as well as other drugs to counterbalance the effects of the disease-related therapies. At this high level of polypharmacy, autoimmune patients, probably more than those in any other disease category (with perhaps the exception of cancer patients receiving chemotherapy), are well aware of the risk/benefit ratio associated with pharmaceuticals. Autoimmune patients manage their diseases (and their therapeutic regimen) with a level of awareness and precision that comes from years of practice and experience. When their therapeutic regimen needs to be changed, either because of potential new therapies or because of the removal of existing therapies from the market, this requires a significant effort on the part of both the patient and the physician to re-establish disease-management equilibrium.

II. Changes in the Healthcare Environment Relevant to Patient Voice and Choice

For healthcare as for life, “The only thing that is constant is change.” As our society evolves, the rate of change in all facets of life, including healthcare, has increased. Relative to healthcare, recent changes in the socio-politico-economic environment within the US have led to what best can be described as an “emphasis and, it could be argued, an overemphasis on the safety implicit in the risk/benefit ratio for pharmaceuticals.”

Although the reasons for this are complex and interconnected and beyond the scope of this paper, contributing factors are without a doubt the changing perceptions of the pharmaceutical industry, pressures from consumer groups, litigation and an increasingly conservative regulatory environment.

The relationship between the FDA and the pharmaceutical industry represents a delicate balancing act between choosing for the American consumer an appropriate therapy with the correct balance of safety and efficacy while, in effect, providing in its regulatory capacity a protective environment in which the pharmaceutical industry can continue to serve patients healthcare needs in the litigious US healthcare environment. Recent events, particularly those leading up to the ultimate withdrawal of Vioxx, have suggested that perhaps the FDA initially favored the industry side of the equation too strongly at the expense of the consumer. Thus, at the risk of oversimplification, the FDA’s current operating paradigm can be viewed as a reaction to a public perception problem, with the rigorous review of both the Cox-2s and other NSAIDs serving as the prime example of the new paradigm. The fact that the FDA, with an acting FDA chairman at the helm, is lacking critical, long-term leadership in some very decisive times could be a contributing factor to the current situation.

To be sure, the public consumes the medications that the FDA approves. And, accordingly, certain consumer groups have pushed for stronger long-term safety concerns for pharmaceuticals. In this regard, both the FDA and the pharmaceutical companies are somewhat limited in predicting long-term safety by the very nature of clinical study design relative to the vagaries represented by use, misuse and concomitant use of pharmaceuticals in the public domain. Given these uncertain results in the true theatre of life for pharmaceuticals, it is not surprising that post-launch issues arise that are not readily apparent in the initial clinical studies required for drug approval. Considering this, Phase IV surveillance of recently introduced therapies is a great idea, although the FDA needs to provide additional guidance on collection, analysis and interpretation of data from these Phase IV studies.

Through all of this, one needs to recognize that consumers are not necessarily patients and that patients need to be entrusted with the responsibility to make decisions regarding their healthcare, as opposed to submitting to a mandate put forth by consumer groups. “One size does not fit all,” particularly in the case of patients with difficult-to-treat diseases such as autoimmune disease. Too often, instead of working with patient advocacy groups toward the common public good, consumer groups see patient advocacy groups as mere protagonists of the pharmaceutical industry rather than as proponents of their individual right to properly manage their own disease.

The pharmaceutical industry has its own public perception problem with which it is struggling to deal. The rising cost of pharmaceuticals, particularly when compared to costs within other countries, is certainly an issue worthy of a separate discussion. It is likely that efforts to approve drug importation will resurface and, as they do, will further tarnish the image of “big pharma.” Direct-to-consumer advertising has brought the patient into the equation and, on a positive note, has increased disease awareness; but on the other hand, it can be perceived as intrusive and potentially damaging to the patient-physician relationship by promoting a specific patient management strategy. And the pharmaceutical industry itself has been unable, either through its member organizations or through its relationships with the FDA and Congress, to favorably alter its tainted public image. The pharmaceutical industry’s reliance on pricing rationales involving the high cost of research and bringing a drug to market have given way to arguments for US pharmaceutical price reductions via a global amortization of research costs rather than the current global research subsidy paid by US healthcare consumers with resultant high prices for pharmaceuticals within the US.

“The issue of safety and what happens when a drug gets out of clinical trial and into the general population is always an issue, and how adverse events are reported and how we learn about the side effects of a drug and the efficacy of a drug, once it’s actually being used in the general population compared with the more selective clinical trial population…I am not exactly sure why the Vioxx, the Celebrex, the Cox-2 inhibitors attract so much attention in the media except that there has been a growing emphasis on the influence of pharmaceutical companies on government, on marketing, and on some of the other areas…And of course a lot of this revolves around the cost of drugs in general.” (Alan J. Balch, Ph.D., Director of Policy and Programs, Friends of Cancer Research, personal communication April, 2005)

III. Implications for Patients, Particularly Autoimmune Disease Patients

There are additional potential constraints to access to pharmaceuticals for US citizens as well. At first read, reimbursement and even practice algorithms that are focused on evidence-based medicine appear as reasonable options. However, such restrictions severely limit the ability of the physician to prescribe medications out of indication and for patients to afford such medications, or both. This is particularly relevant in autoimmune diseases such as lupus. For lupus, new therapeutic advances have not occurred in decades, and the incentive to develop new therapies is limited given the relatively low incidence of the disease. Coupled with the high level of intra-patient variability regarding therapeutic response, this has led to a need to customize treatment with available, marketed therapies, used out of indication.

In addition, formularies are moving toward limiting the total number of prescription medicines available to a patient to manage a specific disease. Given that autoimmune disease patients may require high levels of polypharmacy to treat not only their disease but also side effects produced by their medications, this is an issue of significant concern.

Within the current environment, both existing medications with positive therapeutic patient histories and potential therapies still in clinical development are under increasing regulatory scrutiny involving safety. Safety-related litigation is becoming commonplace. In some cases, the cost of either successfully defending against litigation or settling such litigation, or both, could potentially exceed the cost of developing the drug initially and, even more significantly, the potential return for the drug in the market. A recent example involves the withdrawal of a promising candidate Tysabri for MS therapy from clinical trials based on serious adverse reactions in a subset of individuals. One would hope that efforts are in progress to predetermine suitable patient categories with an acceptable risk-to-benefit ratio and resubmit the product for approval.

Safety and litigation-related concerns could be a powerful incentive for pharmaceutical companies to practice defensive labeling which in turn could impact formulary coverage and reimbursement. A recent example involves the labeling changes for Natrecor. Given these uncertainties, pharmaceutical companies may cease to develop drugs for all but the most potentially lucrative categories and likely would cease to invest in cures for a majority of the identified autoimmune-related diseases. And government is unlikely to take up the research slack:

“The NIH funding picture is always an issue and again this is something that is going to be more directly impacting researchers. The federal research dollars and how they are spent are always an issue, and in this era of flat funding for the NIH and budget crises on the Hill, it’s going to take a lot of work to keep the dollars high enough to sustain the scientific momentum that has been established in fields like genomics and proteonomics and nanotechnology.” (Dr. Alan J. Balch)

Examples of Patients Concerned with Issues of Voice and Choice: The following patients agreed to be interviewed during the course of preparing this position paper:

Donna Di Sante

Autoimmune Disease: Rheumatoid Arthritis

Yr. of First Diagnosis: 1975 or 76

Therapy History: Therapy has included the full gamut of medications usually used in RA treatment including: sulfides, gold injections, NSAIDs, methotrexate, Plaquenil, prednisone, and recently (now discontinued) Remicade and Enbrel.

Current Therapeutic Regimen: Approximately sixteen prescription medications along with a variety of supplements and OTC medications.

Largest issue regarding patient voice and choice: “Don’t take away my medications.”

Judith Whitmire

Disease: Osteoarthritis

Yr. of First Diagnosis: 1985

Therapy History: Aspirin, Clinoril, the full gamut of NSAIDs and proton-pump inhibitors to control the NSAID-induced gastritis. She has tried all available Cox-2s, with best results from Celebrex.

Current Therapeutic Regimen: A variety of medications centered around Celebrex

Largest issue regarding patient voice and choice: “Pain is a big motivator.... …Don’t take away my Celebrex…My family all died of cancer, there is no history of CV disease.”

Kathleen A. Arntsen

Autoimmune Disease: Lupus (and at least six others)

Yr. of First Diagnosis: 1982

Current Therapeutic Regimen: Currently has a therapeutic regimen consisting of nearly 3 dozen medications to treat not only the primary disease(s) but also the treatment-related side effects.

Largest issue regarding patient voice and choice: “Lupus and several other autoimmune diseases are not that common. There hasn’t been a new therapy in over 30 years.” She feels that there is little incentive, fiscal or otherwise, to research new cures, nor bring them to the market in a reasonable period of time.

Donna Fox-Keidel

Autoimmune Disease: Rheumatoid arthritis and scleroderma

Yr. of First Diagnosis: Age 5

Therapeutic History: Literally, the whole gamut of potential therapies for RA from gold therapy to aspirin therapy to prednisone, etc., including several joint replacements.

Current Therapeutic Regimen: Currently Celebrex is the only medication that she takes for rheumatoid arthritis.

Largest issue regarding patient voice and choice: “When the news first came out about Celebrex, I was really scared, I really didn’t want to lose my Celebrex.” The biggest change for her was that she was actually able to gain weight.

Dave Gearing

Autoimmune Disease: Multiple Sclerosis

Yr. of First Diagnosis: 26

Current Disease Status: Confined to a wheelchair, with limited use of hands

Therapeutic History: Has participated in two clinical trials involving new therapies for MS

Current Therapeutic Regimen: Currently uses Avonex Largest issue regarding patient voice and choice: “For someone like me, independent living is key.” He really would like to see another immediate step between independent living and nursing home care. His number one need is to have someone prepare his meals in advance and assist with some personal hygiene and housekeeping issues for a few hours each day. He feels that there is a “critical shortage in home health care which is geared for skilled nursing at a high hourly rate.”

IV. Major Concerns of Patients Regarding Patient Voice and Choice:

All of the patients interviewed indicated that they wanted to be part of the process that determined an appropriate trade-off between safety and patient benefit:

“In recent stories about Vioxx, Celebrex and Bextra, the focus was on the concerns of the government, medical professionals and pharmaceutical companies. I did not see any testimony from patients. These drugs, and I am sure, other prescription medications have been removed from the market without getting a consensus of opinion from representative patients. ...My point is that we, as patients, should have power when in comes to deciding whether or not a drug remains on the market. Someone needs to listen to us. I would take the option of risk to my health in order to enjoy the benefits of being able to go about my life with a body that works, versus being impaired or disabled by rheumatoid arthritis.” (Donna Di Sante)

“Patients like me can be monitored, informed and allowed to take the drug.” (Judith Whitmire) She indicated that even with the risks, her rheumatologist “would still want to use these drugs. He would look at the whole package, i.e., the benefits and the risks and make an informed assessment and a joint decision with the patient; he explains the risk and the patient makes the decision.” If acceptable Cox-2 alternatives were removed from the market, Judith indicated that patients would be left with little recourse but to turn to “narcotic analgesics, both prescribed and illicit, and would also increase their levels of self-medication.”

Kathleen Arntsen says that she has witnessed delays in approval for a potential new drug for lupus--delays that, in her opinion, err on the side of caution, despite the lack of any significant therapeutic advances in lupus therapy for decades. This approval delay potentially could result in “fiscal hardship for the respective company and exacerbate significant delays in marketing and even a possible complete withdrawal of the NDA application.”

Dave Gearing was disappointed with the removal from the market of Tysabri but feels that “the medical community has been quite fair about potential side effects.” Based on feedback from a relative in healthcare, he feels that "anytime you suppress the immune system, it’s so easy to solve one problem and cause ten more. ...Research is so difficult.” David has participated in a number of clinical trials and also has called his state legislators and congressional representatives regarding not only the need for new medications for MS like Tysabri but also the need for funding an intermediate home health care step for individuals with sound mental capabilities but physical handicaps, like him.

V. A Physician’s Perspective Regarding Patient Voice and Choice:

T. Stephen Balch, M.D. Internist Over 20 Yrs. of Experience with Autoimmune Disease Current Member of the AARDA Board of Directors Largest issue regarding patient voice and choice: The need for clear physician/patient communication regarding the benefits and safety issues and shared responsibility for the ultimate choice of a therapeutic regimen.

Dr. Balch has practiced medicine for over twenty years and has successfully avoided litigation through rigorous implementation of clear communication regarding safety and benefits of various therapeutic approaches, along with shared decision-making with patients regarding their therapeutic options.

“Patients are not fearful of side effects.... If anything they are more upset that they cannot use the medications that have benefited them…All medications have side effects, and all patients have to be aware of these side effects, but they also have tremendous benefits. So, if the doctor and the patient work together and utilize the medication, and know the side effects, and can be aware of what side effects to communicate to the patient, then the system works.” (Dr. T. Stephen Balch)

VI. A Summary of the Current Patient Voice and Choice “Problem”

In brief, the current environment has the most unfavorable implications for patients with uncommon diseases requiring multiple medications, with autoimmune-related disease as a prime example. Effective new therapies are few and far between. Therapeutic regimens for autoimmune disease typically are a changing patchwork mosaic of multiple medications that are constantly fine-tuned to avoid and manage “flare-ups.”

The relatively small disease potential afforded by a typical autoimmune disease does not lend itself to justify research spending towards developing new therapies nor towards funding clinical studies targeting novel autoimmune-related indications for existing medications. The latter is particularly of concern, given the current emphasis on evidence-based medicine as a determinant of reimbursement. Given the lack of truly effective therapies for autoimmune disease, potential therapies ar often tried, out of desperation and out of indication. This practice would become less common as the safety-related initiatives outlined in this paper become more commonplace.

VII. Potential Action Items for Patients

Several patients have indicated that they would be willing to assume the liabilities for their therapies if this would allow them to keep their therapeutic options open.

“If physicians and drug companies are worried about law suits, then states should provide a legal form that would allow a patient to acknowledge that they are aware of the risks of a certain therapy, but make a decision to take the therapy. The form could be signed by a patient advocate (either someone that the patient brings with them, or someone assigned to this role in the medical facility.” (Donna Di Sante)

Donna Di Sante also spoke to the need to find, develop, and fund patient spokespersons from various patient advocacy groups and the patient-public at large to provide testimony and feedback to Congress and to the media on the topic of patient voice and choice. Funding for (in her words) this “Patient Voice Alliance” could be sourced via an unrestricted grant from the pharmaceutical industry.

Kathleen Arntsen recognized that not everyone has the time, energy or good fortune to be able to take their talking points directly to Washington where they need to be heard, as she has in recent hearings concerning a new drug for lupus. She does believe that patients, and particularly autoimmune patients, need to voice their concerns and their healthcare needs by writing their congressional and senate leaders and appropriate health-related officials in Washington, as part of an advocacy group and/or as an individual patient.

Judith Whitmire spoke of the need to support technology development in areas such as genotypic testing that assesses potential risk in patients as a way of customizing therapy for each patient. She also, like Donna, would be willing to sign an informed risk consent form. She felt that patients need to be educated about potential risks in a way that does not frighten them away from seeking more effective therapies. As a patient advocate who attended and spoke at the Cox-2 hearings in February, she believes strongly in the need for patients to assert their right to voice and choice.

Donna Fox-Keidel, a volunteer for the Arthritis Foundation and a chairperson for her local Juvenile Arthritis Foundation, was originally scheduled to testify in Washington in mid-February regarding safety issues and Cox-2s. Unfortunately family illness kept her away, but she did manage to get her message out through local news media. Donna believes strongly in a patient’s right to choose the appropriate level of risk, and she believes that the patient needs to voice this choice foremost with their physicians: “Patients should talk to their doctors and communicate that they really want to have the information to make the choice.... It’s their body. It’s their life. If taking that medication is giving them a quality of life that they can live with, then they should be able to do that.” (Donna Fox-Keidel)

To minimize the impact of litigation on patient choices, Donna, like Judith and Donna Di Sante, would be willing to “sign on the dotted line...and that’s what I told my physician. ...I know that these risks may occur, and I know that they are there. ...I would do whatever I have to do.... We know that there are risks, we know that there are side effects, but in my case, the positive outweighs what could be the negative.”

VIII. Encouraging Steps by Pharmaceutical Companies

Guaranteeing patient voice and choice through continued pharmaceutical access is not just a patient issue; it is also an issue for the pharmaceutical industry. Some companies have stepped up to the challenge. For example, Johnson & Johnson has taken the lead in direct-to-consumer advertising and has indicated that it will take a new approach that deals head on with safety issues and put drugs risks on equal footing with drug benefits. It remains to be seen whether other pharmaceutical companies will follow Johnson & Johnson’s lead.

IX. Encouraging Steps by the FDA

A recent article in The Pink Sheet (May 16, 2005, p. 12) indicated that the “FDA will rely on the input of multiple sclerosis patient organizations to help determine the status of Biogen Idec/Edlan’s Tysabri. The launch of Tysabri was suspended on February 28 after reports of three cases of multifocal leukoencephalopathy were seen in clinical trials involving a clinical database of over 3,000 patients. The Acting Director of the Center for Drug Evaluation & Research (CDER), Douglas Throckmorton, indicated that once a full analysis of the Tysabri safety database is completed, FDA plans to rely on patient groups to help decide the appropriate risk/benefit trade-off for Tysabri. The agency has also demonstrated a comfort level with the public discussion of the risk/benefit trade-offs and morbidity/mortality issues associated with Natrecor from J&J/Scios.

X. Summary

It may be difficult for the FDA and for Congress and also for consumer groups to truly appreciate the level of angst and difficulty experienced by patients, particularly autoimmune disease patients, who have responded well to available therapies with associated improvements in their quality of life and even in disease status, when they are informed that their drug of choice is being removed from the market. To be sure that their needs are “part of the risk/benefit equation,” patients need to continue to speak out, indicate their ability and profess their right to work with their physicians to make the right choice to best manage their difficult disease.

American Autoimmune Related Diseases Association

22100 Gratiot Avenue

Eastpointe, MI 49021