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From Access to Evidence: An Advocate’s Journey

Musa Mayer

Address reprint requests to Musa Mayer, 250 West 82^nd St, Apt 42, New York, NY 10024; e-mail: musa{at}echonyc.com.

NINE YEARS ago this spring, I sat in a Long Island courtroom with the rest of my breast cancer support group. We had come in solidarity for our friend Pat, whose insurance company had refused coverage for a second bone marrow transplant, after the first had failed, on the basis that this was an experimental treatment.

Experimental? Surely not, I thought. The insurance company didn’t care about patients; its only concern was the bottom line. When Pat’s doctor took the witness stand, he offered testimony that seemed persuasive to me. At the time, I couldn’t have told you the difference between a phase II study and a phase III randomized clinical trial. All I knew was that many oncologists were recommending this promising treatment to their high-risk and metastatic breast cancer patients.

Pat felt that the transplant was her only hope. It would be cruel to take away that hope, I thought. Members from the local advocacy group turned out in force that day. The press was there, working on yet another story of a young woman fighting for her life.

The judge, a cancer survivor himself, was clearly moved. Pat got her transplant. Six months later, however, she was dead—not from her metastatic breast cancer, but from treatment-induced damage to her bone marrow.

Then, a second friend died following her transplant a few months after that, and I began to read the research myself, and to piece together what the studies actually showed—and what they didn’t show.

Looking back now, I can trace my radicalization as a patient advocate to the troubling discovery that in the case of high-dose chemotherapy with bone-marrow or stem-cell transplant in high-risk and metastatic breast cancer, the tools of science had been subverted by the rush to embrace the treatment. Most disturbing of all to me was the role that advocates had played in guaranteeing broad access to an unproven and highly toxic treatment, effectively sabotaging enrollment in the randomized trials that would have provided a definitive answer years sooner.

This story may not seem relevant to a discussion of the U.S. Food and Drug Administration (FDA) and drug development, because it occurred outside FDA authority, with the use of already-approved drugs. But I believe it offers a bitter lesson about what can and does happen when advocacy and medical practice allow emotion to supplant good science.

What Can Advocates Learn From This?

First, we should learn that new is not necessarily better. New may be worse than standard treatment, or, as in this case, equivalent, but more toxic.

We should learn that more is not necessarily better. Sometimes more of a drug or combination of drugs is just more toxic, not more effective. This can be the case even when the theoretical model behind the treatment has both intuitive appeal and a justifiable scientific rationale. Hauling out the "big guns" of bone-marrow transplant for high-risk and metastatic breast cancer seemed to make sense. It seemed logical to propose that because these high doses of chemotherapy made tumors shrink more than moderate doses—the so-called dose-response curve—patients would do better in the long run. But they did not.

Another lesson is that single-arm phase II studies, no matter how compelling their results appear, contain potential sources of bias, particularly what is called selection bias. The women in these phase II transplant trials who seemed to do so well were not typical of all women with high-risk or metastatic breast cancer. Because of its toxicity, only younger, healthier women who had responded well to chemotherapy were permitted this treatment. No wonder their outcomes looked better when compared with historical controls from other studies of conventional therapy. The intense diagnostic work-up associated with transplant trials also led to "stage migration," in which many patients were upstaged from stage III to stage IV—creating more favorable outcomes for both groups.

We should learn that it’s often impossible to enroll patients onto randomized clinical trials of a popular treatment that is widely available. Understandably, patients don’t want to take the chance of not getting a treatment they believe to be better.

We should learn to be realistic, but not cynical, when assessing motivations. Doctors don’t always make treatment recommendations based on conclusive evidence; they are human, too, and also vulnerable to wishful thinking. So, too, are researchers, who can also become convinced of the validity of their findings in advance of proof. Witnessing the media hype and public relations that can surround drug development, we should be looking critically at the financial and professional interests of all parties involved.

Finally, we should learn that, as advocates, we must use our influence wisely. We have the power to mobilize media and use political pressure to ensure that the treatments we want are available. During the 1990s, laws were passed in a number of states to force insurance companies to pay for bone marrow transplants.

Without regulation and tight control of access, scenarios like this might become common, as reports of new treatments circulate among desperate patients and their families and are picked up by the media.

Ultimately, we all lose if we don’t advance well-designed clinical trials. I believe that what happened with bone marrow transplant in breast cancer is a prime example of what I call "access advocacy," and that this plays an important role in how advocates interact with the FDA and the drug development process.

What Do I Mean by "Access Advocacy"?

Access advocates believe that rapid approval of new drugs is crucial, through fast-tracking, accelerated approvals, personal influence, political and media pressure, legislation, and other mechanisms.

A central focus of access advocacy is obtaining early access to investigational drugs for patients with advanced cancer who have run out of approved treatment options. This is ordinarily accomplished either through single patient investigational new drugs (INDs; often referred to as "compassionate use") or through expanded access programs, both of which must be FDA approved, and made available through the pharmaceutical company. Issues of inequity and special influence often associated with single patient INDs are rarely, if ever, addressed.

Based on extremely limited evidence from responses in phase I trials alone, some access advocates believe that new treatments in the earliest phases of clinical development will save, or at least extend, many lives. They appear to hold idealized views of these drugs, emphasizing positive anecdotes and end-of-life miracles and downplaying toxicities and drug failures.

These same access advocates believe that, ethically, individual patient needs outweigh regulatory concerns with safety and efficacy and that any experimental drug, following a phase I trial, ought to be made available to cancer patients who have exhausted other options and are ineligible for clinical trials. One recent initiative includes special approval and marketing for this purpose, in the hope that being able to sell the drug at a profit to desperate patients would offer an incentive to manufacturers. This petition and subsequent lawsuit against the FDA have garnered significant media attention.

Clinical trials are often perceived by access advocates as representing an unnecessarily complex and drawn-out process, resulting in the loss of many lives that otherwise could have been saved or extended if only patients in need were granted access to drugs under development. Concerns about the effects of early access on enrollment in phase III trials are often minimized, despite examples for which early access has clearly compromised enrollment.

Access advocates may cast themselves in an adversarial role with the FDA. They often perceive the regulatory process as bureaucratic and obstructionist and believe strongly that it does not represent patient interests.

In one memorable example, a Wall Street Journal editorial about the drug Iressa (AstraZeneca, London, UK) last September was titled, "FDA to Patients: Drop Dead."

In Contrast, Let’s Look at What I Call "Evidence-Based Advocacy."

The primary goal of evidence-based advocates is to ensure that good science gets done in the research and development of new and innovative treatments. They see themselves as partners with FDA, researchers, and the drug industry, representing patient perspectives.

Evidence-based advocates believe that all new treatments must be carefully tested for safety and efficacy before approval. They continually stress the need for patient input at every point in the process.

Although the speed of drug development is important, evidence-based advocates believe that evidence should not be sacrificed for speed. They understand that cutting corners now can have unforeseen negative consequences later on.

Evidence-based advocates make it their business to understand enough of the science involved and its increasing complexity to have a realistic view of both the potentials and the drawbacks of new treatments.

They understand that economic pressures and realities play a role in drug development, and they try to be ever-mindful of influences and biases that may creep in, including their own.

Evidence-based advocates focus on what is likely to benefit all patients with cancer equitably. Access to quality care for all patients with cancer is the highest goal. While they applaud innovations in treatment, they also realize that many lives could be saved or extended if only all patients had access to the treatments we already have.

They believe that old paradigms of clinical research must yield to newer methods. For example, tumor shrinkage after treatment may not be a meaningful way to measure the results of a biologic therapy that works to stabilize tumor growth.

Evidence-based advocates are not heartless. They, too, stand helplessly by as friends and family members exhaust their treatment options and die of cancer. So they support expanded access programs for promising drugs before approval, but only if these programs guarantee fair access and do not interfere with the completion of randomized clinical trials.

Because of the complexity of manufacturing a drug or the financial constraints of small companies, however, the amount of available drug may be quite limited early in development, making large expanded access trials impossible. In the Herceptin (Genentech Inc, South San Francisco, CA) lottery, for example, thousands of breast cancer patients with refractory metastatic disease were forced to draw straws each month for a few treatment slots. In such a case, an evidence-based advocate might at least raise the question of whether the available drug might not actually ultimately benefit more patients were it to be used in a clinical trial—for example, in another cancer.

Evidence-based advocates remain sensitive to the need to make exceptions in cases wherein single patient INDs may be warranted—for example, in cancers that are rare or have limited treatment options and little active research. They support research that shows the promise of individualizing cancer treatment, sparing most patients with early cancer the toxicities of systemic treatment, and targeting those whose cancer is most likely to recur with more effective therapies.

Finally, evidence-based advocates try to carefully balance the risks versus the benefits of treatment, realizing that many cancer drugs carry short and long-term side-effects and that, sometimes, important toxicities become apparent only after marketing approval.

I began this presentation with the story of high-dose chemotherapy with bone-marrow or stem-cell transplant in breast cancer, offered as a cautionary tale of what can happen when new treatments are put into use without adequate testing. Some will recall how that story ended—in scandal, malpractice, greed, misjudgment, and profound disappointment, with the profession of medical oncology turning its back on a treatment it had largely embraced, despite some suggestions that, in an as yet undetermined subgroup of patients, this treatment just might be effective. It’s now unlikely we’ll ever know the answer to that question.

Good evidence of efficacy and safety is always a precious commodity in drug development, and never more than right now. In March 2003, I sat as a patient representative when the Oncologic Drugs Advisory Committee of the FDA met to consider eight indications for seven cancer drugs granted accelerated approval, all of which had failed to meet their postmarketing commitments to demonstrate evidence of clinical benefit in randomized, controlled trials. While we considered each indication individually, some overarching explanations soon emerged from the discussion. In some cases, medical practice had changed; in others the pool of prospective trial participants had become vanishingly small. But repeatedly during the two-day meeting, it was clear that enrolling patients onto randomized trials when a drug is available in the marketplace is next to impossible.

In the case of Iressa, a recent recipient of accelerated approval, the drug will be available in the US, but the postmarketing randomized trials will be done abroad (where the drug is not available) to address the problem of trial enrollment, a "solution" that makes some advocates uneasy. From the March Oncologic Drugs Advisory Committee meeting, it was unclear if any drug granted accelerated approval would be withdrawn by the FDA in the case of negative trials or unmet research commitments. That makes us uneasy, too.

Advocates realize full well that we’re at the beginning of a genomic revolution in cancer treatment. We’ve seen the first of a new generation of targeted therapies that work, if not for cure, then for the prolongation of life. Drugs like Herceptin and Gleevec are leading the way, setting a standard of efficacy that has so far proved elusive for other new therapies like Iressa, for which a lack of targeting has resulted in low response rates. We know there will be more effective targeted drugs and that we’ll discover how to use them alone and in combination to transform what is now relatively rapidly fatal illness into more chronic illness and what is now life-threatening into curable. We can almost taste what is to come.

Yet the explosion of molecular knowledge has inevitably led to delays, disappointments, and further complexities. All the while, the media weekly trumpet some new finding that will one day cure cancer. For patients, families, and advocates, the tiny incremental steps of drug development seem even more interminably slow when we sense we are so close to real breakthroughs. It’s agonizing to think these breakthroughs may not come soon enough for most of those we love who are gravely ill today.

That sobering reality is painful enough to contemplate. It will be more painful still if we, as advocates, do not learn from the mistakes we have made in the past. We have all lost people we love dearly. I believe we must see beyond our personal grief and desperation to the greater good, to the larger vision of compassion that emerges from scientific clarity and rigor in drug development.

Invited Commentary: Susan Braun*

In the preceding piece, Musa Mayer provides an excellent overview of the scientific, political, commercial, and procedural complexities that intersect with and frequently collide around issues of increased patient access to new medical treatments.

From Ms Mayer’s standpoint, it would seem that most, if not all advocates for quicker and more equitable access to new, promising but unproven cancer drugs and treatments—"access advocates"—are driven primarily by emotion and wishful thinking for cures and miracles. "Evidence-based advocates" better appreciate the need for careful testing of new drugs and treatments as well as limits on access to them, even in cases where a patient’s conventional cancer treatment options have been exhausted.

At the Susan G. Komen Breast Cancer Foundation, patient advocates do not fall neatly into either the category of access based or evidence-based. There is a middle ground, where a growing public knowledge of the newest advancements in cancer treatments reveals life-saving possibilities, evidence-based proof of efficacy is respected, and concern for the safety of patients remains paramount. No responsible cancer patient advocate would suggest that the "tools of science be subverted by the rush to embrace treatment." Indeed, many of the best, most credible patient advocates base their views on strong scientific findings.

Most responsible cancer patient advocates, including those championed by the Komen Foundation, would align themselves philosophically and emotionally with Ms Mayer’s statement that "evidence-based advocates are for expanded access programs for investigational treatments before [FDA] approval, but only if these programs guarantee fair access and do not interfere with the completion of randomized clinical trials." This is the middle ground, where access and evidence work together for the benefit of all patients, including those who accept that the end of their lives is near.

Early access to investigational drugs for patients who have exhausted all other treatment options is aptly called compassionate use. Most advocates agree that compassionate use of investigational drugs should be approved for patients whose chances of survival are slim. Most patients facing death do not ask for investigational drugs, but instead will opt for palliative care to ease their transition. Consideration should be given to those relatively few cancer patients who are hoping for the extra time and perhaps the enhanced quality of existence an investigational drug or treatment may lend them. Many terminal cancer patients view the gift of a little more time—to complete plans, to remember, to bring closure, and to say goodbye—as a simple and invaluable grace period. Rarely is it viewed as an attempt at a last-minute miracle. The request for an investigational drug can be a patient’s final act of self-determination and dignity.

Ms Mayer’s article emphasizes poignant issues for all of us to consider. In so doing, we recognize the need to continue advocating for patients representing all stages of cancer without spending too much time trying to determine which "type" of advocacy does it best.

AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author indicated no potential conflicts of interest.

NOTES

Adapted from a talk given at a plenary panel titled "The Role of the FDA in the 21^st Century: Safety, Science, and Speed" at the National Breast Cancer Coalition’s Annual Advocacy Training Conference, May 4, 2003.

Submitted August 5, 2003; accepted August 18, 2003.

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