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FDA proposed regulations regarding expanded access to experimental drugs.

On 14th December, 2006 the US Federal Food and Drug Administration (FDA) issued proposed regulations intended to make investigational new drugs more widely available to seriously ill patients with no other treatment options, and to clarify the circumstances and costs for which drug manufacturers may charge for experimental drugs. The proposed regulations are intended to improve patient access to experimental drugs, and increase drug manufacturers' incentive to develop treatments for serious and life-threatening illnesses by permitting manufacturers to charge for a broader range of investigational and expanded access uses than is explicitly permitted under the current regulations.

The FDA has allowed access to experimental therapies since the 1970s but the existing regulations do not adequately describe the full range of access programmes available. Both critics and the Agency believe the regulations have been applied inconsistently and inequitably. (10) The proposed regulations are intended to ensure broad and equitable access to experimental drugs, and to account for the full range of circumstances in which charging for experimental drugs is permissible. (11)

Expanded access to investigational drugs for treatment use

The proposed regulations set out specific criteria, submission requirements, and safeguards for expanded use of investigational drugs for individual patients, intermediate-size patient populations, and treatment IND or treatment protocols. As a general matter, an investigational new drug may be made available for expanded treatment use if the FDA determines that: (1) the patient's serious or immediately life-threatening disease or condition has no satisfactory approved therapy; (2) the potential benefit for the patient justifies the potential risks; and (3) providing therapy will not interfere with the drug's development. (12)

The FDA would allow an investigational drug to be used to treat an individual patient if a licensed physician determines that the probable risk to the patient from the investigational drug is not greater than the probable risk from the patient's disease or condition, and the FDA determines that the patient cannot otherwise obtain the drug (eg the patient cannot participate in a clinical trial of the investigational drug). (13) As the seriousness of the disease increases, less data will be needed to justify expanded use of the investigational drug. For example, when a patient has an immediately life-threatening condition that is not responsive to available therapy, completed Phase I safety testing in humans, together with preliminary evidence suggesting possible effectiveness, would be sufficient to support expanded treatment use. (14)

The FDA would also allow an investigational drug to be used to treat an intermediate-size patient population when there is enough evidence that the drug is safe to justify a clinical trial of the drug and there is at least preliminary clinical evidence of effectiveness. (15) Expanded access may be appropriate for intermediate size patient populations when a drug that is currently being developed represents the only promising therapy for patients with a certain disease or condition, a drug is being developed but certain patients are unable to participate in the clinical trial, or an approved drug is no longer marketed due to safety or other concerns but the benefits of the drug to a specific subset of patients outweigh the risks. (16)

The FDA would permit widespread treatment IND use of an investigational drug if the drug is being investigated in a controlled clinical trial under an IND designed to support a marketing application for the expanded access use (or such clinical trial or trials have been completed), the sponsor is actively pursuing marketing approval for the expanded access use with due diligence, and there is sufficient evidence of safety and effectiveness to support the expanded access. 17 Such evidence would ordinarily consist of data from Phase III trials, but could consist of compelling data from completed Phase II trials. (18)

While the proposed regulations represent an important step towards granting seriously ill patients access to experimental drugs, there is concern that the expanded access will hinder clinical trial recruitment. Recruitment efforts may be impeded by, for example, the prospect that patients can get access to experimental drugs without the risk of being part of a control group. The FDA has attempted to strike a balance between authorising access to promising drugs and ensuring the integrity of the drug approval process but it remains to be seen how this expanded access would affect clinical trial recruitment.

Charging for investigational drugs

Under the proposed regulations, a sponsor could charge for expanded access to an investigational drug if the sponsor: (1) complies with the applicable requirements for the type of use for which charging is requested; (2) provides justification that the amount to be charged reflects only those costs that are permitted to be recovered; and (3) obtains prior written authorisation from the FDA.19 A sponsor who wishes to charge for expanded access must provide reasonable assurance that charging will not interfere with the development of the drug for marketing approval. (20) Unless FDA specifies a shorter period, charging may continue for one year and a sponsor may request that FDA reauthorise charging for additional periods. (21)

The proposed regulations allow a sponsor to recover 'direct costs' of making the investigational drug available and administrative costs directly associated with the expanded access. (22) Direct costs are costs that can be specifically and exclusively attributed to providing the drug for the investigational use and include costs per unit to manufacture the drug, costs to acquire the drug from another manufacturing source, and direct costs to ship and handle the drug. (23)

The FDA acknowledges that providing investigational drugs for treatment use is potentially costly to manufacturers, particularly when the drug is being provided to large patient populations. The proposed cost recovery regulations are intended to offset those costs and encourage drug manufacturers to make investigational drugs available to seriously ill patients. It, however, remains somewhat unclear what costs are recoverable.

For example, there is room for interpretation regarding what constitutes a cost 'specifically and exclusively attributed to providing the drug for the investigational use'. In addition, manufacturers may be reluctant to disclose costs associated with providing an investigational drug to avoid making themselves vulnerable to claims that a market price is too high after a drug is approved.

[c] Reed Smith 2007

References and Notes

(1.) ReedSmith. (2006). US and EU legal and regulatory update. J. Comm. Biotech. 13 (1), 52-63.

(2.) See docs/draft_guideline_pip_2007-02.pdf.

(3.) See advtherapies/docs/com_2005_567_en.pdf and summary in previous Legal and Regulatory Updates (ReedSmith (2006). US and EU legal and regulatory update. J. Comm. Biotech., 12 (3), 242-252.

(4.) The Pharmaceutical Researchers and Manufacturers of America.

(5.) European Biopharmaceutical Enterprises.

(6.) The European Federation of Pharmaceutical Industries and Associations.

(7.) The International Federation of Pharmaceutical Manufacturers and Associations.

(8.) See gowers_review_intellectual_property/gowersreview_index.cfm.

(9.) Available from the publications section of

(10.) See Expanded Access to Investigational Drugs for Treatment Use, 71 Fed. Reg. 75,147, 75,149 (14th December, 2006) (proposed rule).

(11.) See Id; Charging for Investigational Drugs, 71 Fed. Reg. 75,168, 75,169 (14th December, 2006) (proposed rule).

(12.) 21 C.F.R. 312.305 (proposed); 71 Fed. Reg. 75,166.

(13.) 21 C.F.R. 312.310(a) (proposed).

(14.) See 71 Fed. Reg. 75,151.

(15.) See 21 CFR 312.315(b)(2) (proposed).

(16.) See 71 Fed. Reg. 75,154.

(17.) 21 C.F.R. 312.320(a)(1)-(3) (proposed).

(18.) 21 C.F.R. 312.320(a)(3) (proposed).

(19.) 21 C.F.R. 312.8(a)(1)-(3) (proposed).

(20.) 21 C.F.R. 312.8(c)(1) (proposed).

(21.) 21 C.F.R. 312.8(c)(4) (proposed).

(22.) 21 C.F.R. 312.8(d)(1) (proposed).

(23.) 21 C.F.R. 312.8(d)(1)(i) (proposed).
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Title Annotation:NOTES FROM THE US
Author:Smith, Reed
Publication:Journal of Commercial Biotechnology
Geographic Code:1USA
Date:May 1, 2007
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