IPLEX and the Telephone Game”: -[Response ]

Response to “IPLEX and the Telephone Game”:

Conflicting Paradigms

Mihaly Lenart

Blaming the Victim?

In their paper (1), Drs. Richard S. Bedlack, Vicenzo Silani, and Ester Cudkowicz (in the following “Au-thors”) took a critical view at the communication among ALS patients (PALS) and their caregivers. They reprove the spreading of rumors and misconceptions about ALS treatments, specifically treatment with IPLEX . The Authors’ concern raises the following question:

If you are on death row, and are, in addition, facing years of torture, but are given a gleam of hope to delay or even escape the inevitable by following an unproven path, what would you do?

This is namely the dilemma of PALS! They ask the medical community: What are you offering us other than palliative care? Can you tell us anything encouraging other than making vague promises that in some distant future we will have early detection of ALS, effective treatment of its symptoms, or even a cure? The answer is disheartening: ALS is “a dreadful, terminal, neurodegenerative disease to which no cure has been found so far” (1), not even a symptomatic treatment, and all that PALS can hope for now is to slow down the progression of their illness. Given this answer by the medical community, is it then surprising that PALS are keen to listen to other, more optimistic messages, regardless where they come from and how reliable they are? Who can blame them for turning to each other for help and organizing support groups to exchange news, stories, and ideas? Who can blame them if they reach even for the thinnest thread of hope, or believe in unverifiable promises? Who is to blame if they are fed up with dis-appointing statistics and instead listen to promising anecdotes? Who can blame them for amplifying and/or distorting rare success stories? Who can blame them even for gullibility?

Changing Focus

I understand the Authors’ reservation and agree—to a certain degree—with their assessment regarding the danger and potential harm arising from misleading information, but one also needs to understand the desperation of PALS that is fertile soil for myths and false hopes. I grant the positive intentions of the Authors, yet it is hard to empathize with their grumbling about “the telephone game” of PALS, as it is hard to differentiate between attractive, possibly unfounded or unproven suggestions and those with a chance to succeed. This is especially difficult if you are desperate. The Authors don’t blame anyone ex-plicitly, but they do express concern about fast spreading information that gets distorted and misinter-preted by the online grassroots community of PALS. They also seem to be concerned about internet communication fostering unfounded rumors and gossips, in particular about “[l]etters and petitions […] circulated online” (1) or online chat rooms, such as PatientsLikeMe.com. They conclude that “progressive misinformation […] is a growing problem on the internet.” The internet is a fast and efficient tool to spread information. The side effect of its efficiency is distortion that is a symptom of our time, not a fault of the PALS group. The real problem that needs to be addressed is the divide between the medical community and that of PALS, created by the different paradigm each one lives by.

Authors’ Paradigm

The Authors’ concerns are shared by many in the medical community. The “telephone game” players represent a large number of PALS and their care givers who want to be proactive helping themselves and/or their loved ones. When I refer to the medical and PALS communities, it is a simplification, as there are all kinds of people with different backgrounds, experiences, and views involved with or con-cerned about ALS and its treatment. The purpose of this simplification is to analyze the reasons for the divide between the two communities.
The paradigm of the Authors can be characterized by a sign that I once saw in a medical office. It said: “Let’s first establish who the doctor is here and who the patient.” The Authors obviously share this view of exclusive medical authority, as they find solace in the fact “that most patients have tremendous re-spect for the opinion of their treating physician and health care provider” (1). They suggest that only medical doctors and scientists have the knowledge and wisdom to decide what is best for the patient. They seem to view the PALS community as a group of laymen or amateur scientists who often don’t un-derstand the subject and won’t appreciate or respect the rules of scientific research. For example, the Authors write disparagingly about a study of the efficacy of lithium treatment conducted in the PALS community: “Those who wanted to experiment on themselves [with lithium] found physicians to pre-scribe it, and even found an online forum for entering their data (3). Now these lithium ‘data’ (none of which are validated or controlled) have been analyzed and there is reportedly no obvious beneficial ef-fect, which has prompted calls to cease further study of lithium (4)” (1). The Authors are concerned that “this type of misinformation […] could negatively influence enrollment in ongoing and future clinical tri-als in ALS and slow the development of effective treatments for ALS” (1). In other words, PALS meddling with ALS research might harm the struggle of the medical community and their own remedy.

The Authors also believe in objectivity, and that they, unlike PALS, have access to it. They complain that “few objective data […] are available at this time [about IPLEX treatments of PALS],” or that “[n]o objec-tive confirmation of these symptomatic improvements [reported by a patient after an IPLEX treatment] was provided” (1). This view is the foundation of the positivist (objectivist or modernist) paradigm that is based on the premise that knowledge is “out” there, independent of the knower and ready to be dis-covered. Presupposed in this view is that there is one true reality “out” there, which exists independ-ently of the observer (5). Furthermore, we have access to this reality, and we can fragment, study, pre-dict, and control it (6; 7). The traditional scientist’s goal is to find the truth.

Paradigm Change

The positivist paradigm is, however, plagued with contradictions. As von Glasersfeld (5) points out, while trying to access reality, we have been caught in an age long dilemma: On one hand truth is (traditionally) defined as “the perfect match, the flawless representation” of reality (p. 4), but on the other hand, we all live in a closed world defined by genetic, social, cultural, and other constraints. Who then, is to judge “the perfect match with reality”? To answer this question, Western philosophy has overwhelmingly made the assumption that given the right tools, pure reason is able to transcend all constraints and the confines of the human body. Therefore, in traditional science, emotions, and more generally our body, are obstacles to pure reason. As a consequence, the only valid research methods are quantitative, in terms of “objective” data. “Measurement!”, writes Candace Pert, “It is the very foundation of the mod-ern scientific method, the means by which the material world is admitted into existence. Unless we can measure something, science won’t concede it exists, which is why science refuses to deal with such ‘nonthings’ as the emotions, the mind, the soul, or the spirit” (8, p. 21).

In contrast, the so-called constructivist philosophies have adopted a concept of knowledge that is not based on any belief in an accessible objective reality. In the constructivist view, knowing is not matching reality, but rather finding a fit with observations. Constructivist knowledge “is knowledge that human reason derives from experience. It does not represent a picture of the ‘real’ world but provides structure and organization to experience. As such it has an all-important function: It enables us to solve experien-tial problems” (5, p. 5).

The traditional image of a scientist is a “cool, detached, solitary genius, the one who has the answers that others don’t have, as if the truth could be owned” (8, p. 315). Gergen (9) mentions the work of (re-nowned sociologists) Bruno Latour and Stephen Woolgar, who observed scientists at work at the Salk In-stitute of Biological Studies. After months of observation, they concluded that “what counts as objective truth is not the result of rationally subjecting hypotheses to empirical test, but emerges from a network of social agreements” (p. 93). Thus, if the narratives of PALS are myths, then the objectivity of experi-ments and data is also a myth, for the questions scientists ask themselves, the theories they formulate, and the choice of tools and methods to prove these theories (assumptions) are inherently subjective or biased in the sense that they all depend on social agreements and the intentions and values of the ex-perimenter. Due to the complexity and characteristics of medical problems and the large variety of symptoms, even from a positivist point of view, medical science in general and ALS research in particular is prone to such bias. Scientists commonly use quantitative methods, especially mathematical models, to claim objectivity. But these methods only obscure bias. Thus, the issue is not objectivity, but intention or concern. While the medical community is concerned about helping the entire group of PALS and has a long-range perspective, individual PALS are fighting for their own immediate survival. Problems arise when there is a lack of mutual understanding and acceptance of the concerns of the other.

Implications

The PALS community is questioning medical authority and demanding to be treated as equals as well as involved in ALS-related activities. The proactive stance of the PALS community came about by free ac-cess to information and the unprecedented democracy of the internet: “the information boundaries that previously existed have been gradually breaking down; more patients and their families have become more aggressive in determining their own treatments” (10). Patients want to take control of their lives by networking and learning. PALS and their caretakers increasingly want to play an active role in the in-formation exchange and the decision making process. The “telephone game” paper (1) confirms that in-formation is already flowing between the medical and PALS community. However, the authoritarian tone of the paper indicates that this is not an exchange between equals. The Authors suggest that the medical community has the proper knowledge and right judgment about how to best serve the interests of PALS, for instance by “denouncing or at least severely minimizing a grass roots approach for the use of a biotech treatment [i.e., IPLEX]” (10).
Admittedly, the free-flow of information has pitfalls, such as “possibly erroneous information transmit-ted, inappropriate use of otherwise good information […], a lynch-mob mentality that possibly forces the medical establishment to embrace or at least reluctantly provide such treatment” (10). Yet, discred-iting or distrusting the PALS community kills free communication. The Authors intend to “do a better job distributing information to PALS on the many benefits of” various patient supports and “educate PALS on how to distinguish myth from reality” (1). Thus, the medical community is the one that has access to and defends “reality” against dangerous myths. The presupposition is that PALS cannot be trusted, as they are misguided and misinformed.
The PALS community also distrusts the medical community, as priorities sometimes diverge. The “small but well-documented case series [that] showed potential slowing of ALS progression on lithium” (1) is a good example.

Even within the Authors’ own paradigm, the small number of “subjects” (sixteen PALS) in the study (12) who received lithium (as well as riluzole ) is indeed too small to draw any meaningful conclusion. Yet, it was published and, subsequently, no one in the medical community found it neces-sary to scrutinize its findings. This suggests that the sixteen authors of the lithium study (12) were more concerned about “publish-or-perish” than the impact of their paper or the danger of creating false ex-pectations among PALS. Upon witnessing so much noise about lithium on the internet, why did the medical community keep still? How can the Authors (in hindsight!) criticize the PALS community for ini-tiating and self-conducting a study, if the medical community remained silent while negative experi-ences with lithium treatment were piling up?

The unfolding story of IPLEX also raises unanswered questions—to the dismay of the PALS community. In Italy, IPLEX treatment of PALS has been going on for over two years. “In the meantime, Insmed [Inc., the manufacturer of IPLEX] collected data from PALS in Italy treated with IPLEX, and preliminary results have been recently circulated inside AIFA [Agenzia Italiana del Farmaco], the ALS experts of the Italian Commission and AISLA [Associazione Italiana Sclerosi Laterale Amiotrofica]” (1). Yet, “[t]hese uncon-trolled data have not been officially released” (1). While the medical community must have been aware of the anxiety and high expectations of PALS about IPLEX, how is it possible that no information has been released so far? Is it then surprising if such secrecy fuels suspicion, guesses, speculations, and myths? The Authors write: “We could [italics mine] accomplish this [i.e., the release of preclinical and early clinical data related to IPLEX] via a letter on behalf of the World Federation of Neurology Research Group on ALS (WFN/ALS), the ALS Research Group (ALSRG), or the European ALS Consortium (EALSC)” (1). Why do the Authors, who are concerned about “separating myth from reality on the internet” (1), offer only a conditional “could” instead of a declarative “will” or imperative “must”? And why only now, after more than two years of trial? Also, the patent dispute surrounding IPLEX demonstrates the dis-crepancies between the Authors’ concerns and that of PALS, as in spite of its numerous legal and finan-cial aspects, the Authors mention this only casually. While the Authors are deeply concerned about the communication among PALS regarding ALS treatments, they don’t even mention the extensive online discussions of PALS about the serious legal and ethical issues prior to the agreement (SA-Amendment) of the pharmaceutical companies involved to lift the court ordered restriction on the distribution of IPLEX.
Informed consent is a widely accepted ethical and legal practice. Patients with untreatable terminal ill-nesses often take risks by consenting to untested and unproven treatments. As long as they are fully in-formed about the known benefits and risks (of morally and medically justifiable harms) involved, con-sented use of experimental treatments is neither ethically nor legally objectionable. In fact, usually phy-sicians learn first about new experimental treatments and offer them to patients who have no other vi-able options. Yet, except for the selected group of Italian patients, PALS cannot obtain IPLEX, even if they consent to it.

IPLEX is a complex of recombinant human insulin-like growth factor (IGF-1) and its predominant binding protein, IGFBP-3. “[It] was originally FDA [Food and Drug Administration] approved for severe short stature due to Primary IGF Deficiency (IGFD), and has been through varied stages of clinical testing for multiple other indications, including premature birth retinopathy, HARS, Noonan Syndrome, Myotonic Muscular Dystrophy, insulin resistance, Lephrechaunism and Laron Syndrome. The drug is safe and well tolerated, even in premature infants. Upon the release of Iplex in November 2006, it was shortly there-after off-label prescribed for twelve ALS patients in the US. Of these, eight were carefully monitored dur-ing the period of their Iplex usage between January-March 2007” (15), before IPLEX was recalled be-cause of the above mentioned patent dispute. During this short time, each of these patients experi-enced remarkable gains in multiple areas of function “including but not limited to, improvement in weight gain, respiration capacity, hand and foot motor function, minimized spasticity and rigidity and reduction of untoward fasciculations” (15).
In spite of the SA-Amendment, IPLEX is unavailable and obtaining it for ALS treatment requires FDA ap-proval. Insmed advises PALS that “a physician may submit an IND [Investigational New Drug] application to FDA for the treatment of an individual patient under a Single Patient IND, sometimes known as ‘Com-passionate Use’” (13).

Recently, a few physicians submitted Single Patient INDs for their respective pa-tients. FDA rejected all these applications arguing in essence that a) “[a]lthough […] there is a single con-trolled trial of IGF-1 in patients with ALS in which it has been shown to be superior to placebo, there are at least several other adequately designed and conducted trials of IGF-1 in which effectiveness has not been demonstrated.” Also, “there has been a suggestion of” and “it is reasonable to be concerned that the potential signal for [serious harms] associated with IGF-1 may be applicable to Iplex” and b) “given the intense interest in this compound in the ALS community, we [the FDA] believe that granting a single-patient INDs to even a few sponsors at this time would result in such a widespread use that adequately controlled trials would become virtually impossible” (16).

The latter, of course, is the same concern the Authors described in their “telephone game” paper (1). In case of a Single Patient IND or Compassionate Use, such a concern is hardly legitimate for a regulatory agency whose task, according to the FDA’s own website, is to determine “if the product is reasonably safe for initial use in humans” (17). Regarding a), FDA admits that “the evidence of the lack of benefit and possible harm of IGF-1 is not definitive. Moreover, Iplex is not identical to IGF-1” (16). Nevertheless, FDA believes “that the public health would best be served by the conduct of adequate and well-controlled trials of Iplex, so that definitive answers can be obtained about its utility as a treatment for patients with ALS” (16). Alas, such trials take years that most PALS don’t have and cost millions of dollars which are beyond the means of PALS or their physicians. Thus, PALS are trapped between FDA request-ing “adequately controlled trials” and Insmed that “[a]t the present time […] cannot predict if or when it will conduct a clinical trial to study IPLEX™ in the ALS population” (13).

Statistics are commonly used mathematical models in medicine. While they are extremely useful for re-search, anecdotal evidence is sometimes more meaningful for PALS. An ALS patient might care more about the account of a fellow ALS patient who experienced “rapid improvements,” than the lack of “ob-jective confirmation of […] symptomatic improvements” (1). From an ALS patient’s point of view, does it really matter whether IPLEX “objectively” and measurably improved the symptoms of someone, or s/he just “felt like [her/his] body was under a seismic shift and IPLEX was jolting the foundation of the dis-ease” (1)? If all that IPLEX is doing is creating such feelings, then it is far more than anything else the medical community presently offers.

In spite of the medical community’s misgivings, PALS are also trying unorthodox methods, such as alter-native and Traditional Chinese Medicine, to ease their pains. Without offering any alternatives, how can anyone discourage PALS from trying medically unproven methods, as long as they are relatively harm-less? If they turn out to be ineffective, the only possible harm is disappointment. Yet, disappointment is still better than succumbing passively to this devastating illness. As long as there is something to try, there is also hope. As long as there is hope, depression, a common ALS symptom, can be kept at bay. IPLEX is a drug that has been thoroughly tested and approved for other applications than ALS. Yet, it was found safe and well tolerated, even in premature infants, and apparently did help a few PALS. Thus, it is another hope that keeps PALS going.

Opportunity

IPLEX epitomizes the moral dilemma of balancing individual vs. group interests. How do we as a society decide between compassionate use of a drug to help terminally ill individuals today and scientific re-search to help patients in the future? How do we decide what is morally, ethically, and economically ac-ceptable? Who should make such decisions? Can physicians alone decide? Is the medical community in a position to find morally and socially satisfactory answers? Shouldn’t we rather have open democratic discussions and decide by listening to all parties involved? In particular, shouldn’t PALS, the victims and experts of this terrible disease, be involved in such decisions?

The misunderstandings and mistrust between the medical and PALS communities are very unfortunate, as there are wonderful people on both sides of the divide who are moved by the unspeakable human tragedy of PALS. Every one of them has the same goal of helping PALS, even if their philosophy and ap-proach are different. Since the medical community has the power and means to influence research and the pharmaceutical industry, I applaud the Authors for recognizing that it is the medical community that needs to take the initiative and change. However, where they see problems, I see opportunities. The grassroots organizations of PALS are an enormous force to reach and mobilize patients and care givers. In addition, the Internet is a magnificent tool to communicate and distribute information instantane-ously. Thus, scientists and pharmaceutical companies have an opportunity to build a large community to work with for collecting information, disseminating data, and ultimately help PALS more effectively. Working closely with the PALS community would also minimize misinformation. PALS and their caregiv-ers are also extremely driven, cooperative, and knowledgeable. They might lack medical knowledge, but they live ALS every single day, which is knowledge the medical community doesn’t have. Thus, there is an opportunity for change of attitudes and cooperation between the medical community and the grass-roots organizations of PALS. All it needs is more openness and trust.

Acknowledgment

I am grateful to all PALS, particularly my brother-in-law, Dr. Gabriel Pasztor, for giving life a new mean-ing through their attitude of bravely fighting against this terrible disease. I also thank them for their in-put and encouragement to publish this paper. Dr. Peter Tarjan provided feedback and suggestions for improvement from a biomedical, my wife, Dr. Ana Pasztor, from philosophical and linguistic, and Dr. Olin Hardiman from a medical and editorial point of view.

Stephen Byer, whose selfless mission to help PALS and his energy and dedication also inspired me greatly.