Patient Demands vs. Product Development

As the public clamors for early access to promising new drugs, sponsors worry about the consequences of experimental therapy conducted outside of controlled trials.

Every researcher and study sponsor dreams of announcing promising results from early clinical studies of a new treatment, but the excitement can turn into a nightmare if the company is unable to deal with requests from dying patients for early access to a wonder drug. Instead of garnering kudos for investing in high-risk research with the hope of identifying a life-saving treatment, a company may find itself the subject of a media expos or a committee hearing on Capitol Hill.

The Food and Drug Administration (FDA) allows certain patients to obtain therapies before approval under compassionate use and treatment IND (Investigational New Drug) programs. But sponsors face the dilemma that widespread use of an experimental therapy outside of controlled trials may generate adverse events and negative results that can make it difficult to gain market approval for the new product. Manufacturers also often have very small amounts of clinical supplies and cannot provide many individuals with a new product that is still in clinical trials.

Patient empowerment is prompting regulators, health care providers, and sponsors to address these issues. FDA is examining the impact of early access programs on studiesand sees a need to clarify its policies. Pharmaceutical companies are exploring options for providing needy patients with access to experimental products as equitably as possible. A related goal is to encourage more patients to enroll in clinical studies, which may be encouraged by expanded information on trial options and improvement in coverage of health care costs related to clinical trial participation.

Questions and concerns
Spurred by complaints about access from patients, Representative Dan Burton (Republican, Illinois), chairman of the House Committee on Government Reform, held a hearing 20 June 2001 to explore whether FDA policies or industry practices are denying patients access to experimental therapies that might save lives. Reacting to a 60 Minutes report (6 May 2001), Burton wanted to know why a small biotech company, ImClone, was able to provide a new cancer therapy to some patients but not others, and whether government red tape was the culprit.

Robert Temple, associate director for medical policy at FDAs Center for Drug Evaluation and Research (CDER), explained that FDA cannot compel a manufacturer to provide an experimental therapy to patients and that limited supply is a prime reason that companies often fail to do so. Manufacturers make small amounts of a test therapy for early drug studies, and scaling up to larger batches is expensive and not considered reasonable until there begins to be evidence that the drug is of value, Temple pointed out. Moreover, the process of packing and shipping drugs for single-patient use on an emergent basis can be very disruptive for companies conducting clinical trials.

Clinical trial concerns. Another concern is that broad early access programs may hurt clinical trial enrollment and study results. If a test drug is readily available, patients may be reluctant to participate in a formal study where they may receive an older therapy or none at all, Temple explained. Use of investigational drugs in less controlled settings and in patients with very advanced disease states may increase adverse reactions that raise questions about the therapys safety and efficacy. Temple said that FDA expects very low response rates in patients who have previously received multiple therapies and that this does not damage the drugs chance for approval, but sponsors are wary of generating a large volume of negative results.

Informing the public. FDAs Oncologic Drugs Advisory Committee (ODAC) addressed these issues at meetings in December 2000 and June 2001 as part of an effort to expand information to the public and to physicians about access to investigational cancer drugs. Agency officials asked the panel for advice on when it is appropriate for FDA to allow investigational drugs to be used for the treatment of individual cancer patientswhat is often referred to as compassionate use or a single-patient IND study. FDA permits an individual investigator to treat a patient by filing a single-patient IND that refers to an existing commercial IND.

Interestingly enough, several patient groups opposed widespread individual access, emphasizing that it is important to develop new therapies rationally and that individual treatment should be deferred until there is adequate information to support a specific use. FDA plans to hold a larger meeting with the National Cancer Institute (NCI), academics, and patient groups to develop consensus on early-access issues. One topic is whether third parties such as NCI could administer expanded access programs for manufacturers. At the House hearing, Burton praised AstraZenecas expanded access protocol for its lung cancer treatment IRESSA, which is administered by the National Organization for Rare Disorders.

Temple also said that FDA is working on a new rule to update and clarify what avenues are available for sponsors to offer patients access to experimental therapies outside clinical trials. FDAs Treatment IND rule was finalized in 1987 to make unapproved but promising drugslargely AIDS therapiesmore broadly available to patients needing them once clinical studies provide some evidence of efficacy. The revised rule would implement provisions in the FDA Modernization Act of 1997 (FDAMA), which codified existing FDA regulations and policies to expand patient access to experimental drugs and devices. In addition to treatment INDs, those regulations cover emergency situations and individual access. FDA also has been working to expand access to investigational cancer therapies that have been approved in other countries. All these cases, Temple emphasized, depend on obtaining evidence of safety and effectiveness to support a proposed use.

Pressure on manufacturing
Clearer FDA access policies, however, may not help sponsors that cannot produce enough of a test therapy to be able to distribute it to patients outside clinical trials. At the Burton hearing, ImClone president Samuel Waksal described how his company has tried, but failed, to provide its promising cancer therapyIMC-C225 (cetuximab)to patients. During five years of clinical research, the drug was tested in more than 700 individuals, including 30 compassionate use patients. But after publishing positive results from clinical trials in May 2000, the company received requests for the drug from 8500 patients. The company tried to handle the volume by putting the names on a first-come, first-served list, but had to close down its compassionate use program when the list had more people than it could possibly serve.

The main problem, Waksal explained, is that his small company cannot produce enough of the product to meet patient demand while continuing to conduct clinical trials. As a protein derived from a living cell line, IMC-C225 must be produced under highly controlled conditions, with each step thoroughly documented to meet strict FDA guidelines. To obtain initial clinical supplies, ImClone built its own 55,000-square-foot pilot manufacturing facility. As trials and outside demand grew, the company contracted with Lonza Biologics to produce additional product at its New Hampshire contract manufacturing facility.

In the end, the company decided that its best strategy was to concentrate on getting the drug approved by FDA and to increase product supply as expeditiously as possible. ImClone filed a rolling Biologics License Application (BLA) with FDAs Center for Biologics Evaluation and Research (CBER) in order to gain conditional FDA approval for a limited indication for the therapy in a year. The company also is investing $55 million to construct an 80,000-square-foot commercial manufacturing facility next to its New Jersey pilot plant, in anticipation of market approval. When the new plant is fully operational next year, ImClone hopes to revive its compassionate use or a broader expanded access program for patients, Waksal told the Burton committee. In the meantime, the company has had to turn down emotional pleas from patients and their families. To avoid such problems and ensure that the company can meet future commercial demand for C225, ImClone is weighing construction of another manufacturing facility with a 90,000-liter fermentation capacity, which will cost about $200 million.

Clinical trials data bank
As ImClone foundand FDA officials and many patient advocates agreethe best way for patients to receive promising but unproven therapies is by participating in a controlled clinical trial, particularly at early stages in product testing and development. Clinical trials provide appropriate subject protections and maximize the collection of useful information about the product, which can benefit the entire patient population, Temple explained. FDAs Office of Special Health Issues (OSHI) helps provide information to cancer patients and other individuals on research and access opportunities.

Sponsors slow to sign up. OSHI efforts to steer patients to suitable clinical trials could be enhanced by expansion of the FDA-NIH data bank on clinical trials for therapies to treat serious or life-threatening diseases (www.clinicaltrials.gov), which FDAMA required the agency to establish. Most of some 4500 actively recruiting trials now on the Web site come from NIH and academic institutions, with only 157 sponsored by industry. Manufacturers say they have been waiting for FDA to issue a final guidance on what data should be included on the Web site and how to submit it. FDA took a step toward meeting that request by publishing a draft guidance describing procedures for submitting protocol information to the clinical trials data bank.¹ A draft guidance issued 29 March 2000 outlined the types of trials and information that sponsors should list.² FDA hopes to issue a final guidance by year-end. In the meantime, the agency is urging sponsors to list studies voluntarily and has been disappointed that so few choose to do so.

Covering medical costs
Another development likely to increase patient participation in clinical studies is expansion of both public and private coverage for medical costs associated with experimental treatment. Most insurers and managed care plans now provide beneficiaries with coverage for costs associated with clinical trials, a trend encouraged by Congress and patient advocates. The patients bill of rights legislation approved by the Senate in July also specifies that health plans should cover the traditional costs of critically ill patients in clinical trials and offers protection for insurers from liability if there are problems with the outcome of a trial.

Last year, the Clinton administration issued a policy supporting Medicare reimbursement of patient care costs associated with participation in certain clinical trials. To implement the policy, the Health Care Financing Administration (now called the Centers for Medicare and Medicaid ServicesCMS) published a national coverage statement in September 2000 spelling out the criteria a study has to meet to qualify for Medicare coverage. A main requirement is that the study evaluate a product or service covered by Medicare. That could exclude outpatient prescription drugs and many medical productsunless Congress establishes a Medicare prescription drug benefit. The policy also says, however, that Medicare will cover costs associated with trials funded by NIH and other government agencies or conducted under an IND approved by FDA.

A government panel is supposed to decide what other clinical trials warrant Medicare coverage, which should provide some needed clarification on the program. In the past, Medicare carriers often paid for claims for routine care associated with clinical trials. That was on the decline, though, because federal agencies have been scrutinizing reimbursement and claims more closely. The administrations more explicit coverage policy is needed if more elderly patients are to enroll in clinical studies.

References
1. Food and Drug Administration, draft guidance, Information Program on Clinical Trials for Serious or Life-Threatening Diseases: Implementation Plan, Federal Register 66 (131), 3579835799 (9 July 2001); also available at www.access.gpo.gov/nara/cfr.

2. Food and Drug Administration, draft guidance, Draft Guidance for Industry on Information Program on Clinical Trials for Serious or Life-Threatening Diseases: Establishment of a Data Bank; Availability, Federal Register 65 (61), 1662016623 (29 March 2000); also available at www.access.gpo.gov/nara/cfr.