GLG News by Evan Siegel, MPhil, PhD

Implications: The issues associated with expensive therapeutics are multifaceted and involve personal, professional and societal components. Value related to medical treatment is uniquely assessed by each individual with respect to his/her financial burden, overall lifestyle and quality of life, societal role, and belief structure. Society itself is beset with contrary stakeholders in the insurance, governmental, medical and belief-centered establishments. This article is important in that it lays out some fundamental questions that wealthy countries face with respect to cost vs. benefit for new therapies in an environment relatively little constrained by cost-containment in the medical arena.

Analysis: The risk vs. benefit to profit-making enterprises in the medical field is usually drawn sharply to the risk side of the equation when one looks at the number of preclnical and clinical programs initiated vs. the rate of succesful therapies introduced each year, and over five to ten year periods in the U.S. However, for those medical products which are approved, particulalry in the oncology arena, off-label uses greatly multiply the sales of drugs and biologics over what one would expect for the approved uses. Even for labeled conditions, sales can be massive, due to the ever-present hopefulness inherent in oncology patients and their physicians and the emotional toll that this disease complex takes on the paitnets and their famillies. The "real" benefit to the patient may be minimal or major, depending on the relative proportion of off-label vs. within-label uses of a therapeutic and the perception of benefit seen by the stakholders involved in the process.

In the real world of medicine benefit, real or imagined, may be of a greater magnitude than seen in pre-approval clnical trials or of a lesser magnitude. It is to pharmaceutical firms' benefit to prepare for these real-world issues when developing and marketing new and expensive therapies and to be careful of either deliberately or subliminally overseelling benefit. The newly institued and expanded clinical trials reporting laws and the enabling regulations to come will provide patients and helthcare providers with a new armamentarium to assess perceived benefit vs. cost for approved products. This should provide somewhat of a new tool for making decisions and use of new therapies.

Implications: 1. Sponsors need to be "squeaky clean" with respect to their assessment of signals of toxicity in drug develpment programs. 2. This assessment should be made at the preclinical and early clinical stages of the process, irrespective of political and financial considerations. 3. The per cent of failures in Phase 2 and 3 will be higher unless programs are honestly and thoroughly assessed according to the above. Even so, there will likely be more failures in late-stage programs as clinical data are generated. The FDA will spend more time and effort on safety assessment to avoid large populations being exposed in the marketing environment to new drugs.

Analysis: Until valid computerized or in vitro models are developed that can accurately and reproducibly assess, in advance,  the potential for long-term safety (particular cardiovascular) of new long-term treatments for chronic or chronic progressive disease will need to be examined more aggresivly by sponsors, not just FDA reviewers. Otherwise, more and more programs will be delayed in approval; have imposed "black box" warnings on product labels; lead to failed drugs in the postmarketing environment; and fail prior to approval after most clinical data have been generated. One way to avoid this is for sponsors to aggresively assess, in the preclinical and early clinical environments, potential safety signals that could lead to trouble later. Political considerations, investor concerns and other non-data based issues should not mitigate against a clear, aggresive and intensive assessment of safety signals early in drug development. The waste of time, money and resources could be avoided by the "killing," particularly of "me-too" programs, should signals of toxicity be identified and dealt with early on.

Implications: Overseas manufacturing controls for both APIs and finished drug products will need to be improved and the FDA will closely monitor compliance in an increased fashion. Drug regulation itself is not likely to change, but more inspections and more thorough review of DMFs and information submitted in support of late-stage INDs and NDAs/BLAs will occur. The FDA has been lax in assuring that the veritable explosion of outsourcing of raw material and API manufacture to third-world and emerging nations has been closely monitored for compliance with purity, potency and other requirements.

Analysis: The strong pressures for control of drug pricing by goernment, insurers and healthcare containment advocates have led to a movement towards outsoucing of raw materials, API and dinfished drug products to India, China and other countries outside of the US and Europe. The controls on quality have not followed suit in intensity, either by the pharmaceutical firms or the FDA. This has led to an increased probability that contaminated or lower quality material may appear in at least some batches of pharmaceuticals to which patients may be exposed. The laws and regulations to control this situation are in place; the FDA's priorities have, however, not included stepped up policing of this situation to assure product quality. The will is there, but the resources and finances are limited. Generic manufacturers might be seen as being more vulnerable to the negative effects of this situation; however, the heparin episodes have shown that even major pharma companies have been attempting to minimize their costs by moving to somewhat questionable suppliers. The answer to this qundary is more internal inspections and audits of raw materials and API by firms themselves as well as stepped up compliance by the FDA. The recent move to place FDA offices in China is a step in the right direction.

Implications: 1. The results are intriguing, but the clinical relevance for the large number of patients who could be exposed in the real-life clinical situation is uncertain. 2. The hypotheses for thsi program early-on seem to be supported by the phase 3 data to date, i.e., the nitro-comopounds may have actions that are different than their parent compounds. 3. It will be inteesting to see across finished studies what the actual effects on blood pressure may be.

Analysis: These results are intriguing from both a hypothetical and practical point of view for patient health and welfare. It remains to be seen whether the hypotensive effect is conssitent across finished phase 3 studies and, eventually, in the post-marketing environment. It must be remembered that a decrease in DBP or SBP is to be generally considered a positive effect (as long as a precipitous hypotensive effect is not seen); however, statistical significance is not the same as clinical relevance for the average patient with osteoarthritis being treated with an NSAID. Thus, the actual data from the completed studies will need to be evaluated to ascertain if a statistically significant result in lowering of SBP and/or DBP for Naprocinod vs. e.g., Napoxen is really clinically meaningful to the majority of patients under treatment for osteoarthritis. The FDA wilil be the final arbiter of any labeling claim that the Sponsor wishes to make for the product and it is likely that an FDA Advisory Committee will be asked to comment on such a claim.

Implications: 1. Metastatic melanoma in Stage IV is difficutl to treat. 2. Previous interventions have proven almost worthless 3. The succesful SPA agreement is an important regulatory step for the program. 4. Data will take years to develop, validate, and translate into an approved product.

Analysis: The advent of any new, promosing therapy, with an acceptable safety profile and clinically relevant efficacy is important for Stage IV melanoma. The conclusion of a succesful SPA is important, as it will assure that, should the protocol be executed precisely, in accordance with Good Clinical Practice, and with statistically significant and clinically relevant data in patients (e.g., meeting the primary endpoints), the completed study could form an important portion of a marketing application to the FDA, suitable for review for a potential approval. It must be mentioned, however, that virtually all such porducts have failed in the clinic and there are years of data develpment, validation, analysis and reporting ahead, before a product could be approved stemming from this research. The FDA is likely to sit up and take notice, however, if the therapaeutic index from data-driven analysis show promise for this disease in Stage IV. The possibility of treatment in earlier stages should not be discounted as well.

Implications: This announcement indicates that clinical development can now proceed under the IND for all outstanding and recently submitted protocols. It does not mean that the initial reason for clinical hold has been fully satisfied throughout the rest of the clinical development program. That will be dtermined by the data emergent results from the clinical tirals and any ongoing or planned preclinical studies. Likely there was a safety issue, either clinicaly or nonclinical that caused the hold. Future work may be needed to assure that the program can proceed to substantial evidence trials.

Analysis: Analysts and others should look for any further clinical holds or other delays in the program. Until all data have been generated from preclinical and clinical trials, an NDA or BLA submitted and accepted for filing, the program cannot be considered to be ready for full FDA review for potential approval.

Implications: The user-friendly and health care provider comfort aspects of an product with otherwise proven safety and efficacy must be considered when deciding how, when, and in what manner to develop f drug product. Despite the desirability of a non-injectibel insulin, the inhaled route of administration and acceptability of the formulation must be carefully examined in the real-world, and not just clinical trial, environments. This firm, despite its long history and expertise, missed the boat.

Analysis: Careful market analysis, as well as a thorough review of clinical tiral data, outcomes, and acceptability of the dosage form, would have likely provided a go/no-go decision earlier for the product. It does not good to have an expensive approval that fails in the marketplace. Writing off development costs without a spectacular failure in clinical use acceptability would be an important consideration for those to follow.